Heteroaryl-substituted 1,3-dihydroindol-2-one derivatives and medicaments containing them

ABSTRACT

The present invention relates to novel 1,3-dihydroindol-2-one (oxindole) derivatives of the formula (I) in which A, R 3 , R 4 , R 5 , R 6 , and R 7  are defined according to claim 1, and to medicaments containing them for the treatment of diseases. In particular, the novel oxindole derivatives can be used for the control and/or prophylaxis of various vasopressin-dependent or oxytocin-dependent diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a divisional of U.S. patent application Ser. No. 10/574,211,filed on Jan. 22, 2007, which is the U.S. National Stage ofInternational Patent Application No. PCT/EP2004/010940, filed on Sep.30, 2004, which is a continuation-in-part of U.S. patent applicationSer. No. 10/675,300, filed on Sep. 30, 2003, the contents of all ofwhich are hereby incorporated by reference.

The present invention relates to novel 1,3-dihydroindol-2-one (oxindole)derivatives and to medicaments containing them for the treatment ofdiseases.

The role of vasopressin in various pathological states has been thesubject of intensive research in recent years, and the selectiveantagonism of the various vasopressin receptors opens up novel clinicalprospects. At present, three receptors (V1a, V1b or V3 and V2) by whichvasopressin mediates its effect are known. In contrast to the other tworeceptors, the vasopressin V1b receptor is mainly found in the CNS. Thissuggests that in particular CNS effects of vasopressin are mediated bythe V1b receptor. Thus, it has also been, found that an antagonist ofthe V1b receptor shows anxiolytic and antidepressant effects (Griebel etal., PNAS 99, 6370 (2002); Serradeil-Le Gal et al., J. Pharm. Exp. Ther.300, 1122 (2002)). Since the models used allow a certain forecast of aclinical effect, antagonists of the vasopressin V1b receptor might beuseful for the treatment of emotional disturbances, e.g., stress,anxiety and depression.

WO 93/15051 and WO 98/25901 have already described1-phenylsulfonyl-1,3-dihydro-2H-indol-2-ones in which the oxindoleframework is substituted in position 3 by two alkyl radicals, which mayalso be a cycloalkyl radical (spiro linkage), as ligands of vasopressinreceptors. An alternative possibility is for the spiro ring to containheteroatoms such as oxygen and nitrogen (optionally with substituents).

WO 95/18105 describes 1-phenylsulfonyl-1,3-dihydro-2H-indol-2-ones whichhave a nitrogen atom in position 3 as ligands of vasopressin receptors.Additionally bonded in position 3 are radicals which may be alkyl,cycloalkyl, phenyl or benzyl radicals (optionally with substituents ineach case).

Other publications describe compounds which have nitrogen-containingrings (e.g., proline, homoproline, morpholine, tetrahydroisoquinoline,dihydroindole; optionally with substituents in each case) bonded viatheir nitrogen atom to position 3 of the oxindole framework, but whichhave phenylsulfonyl or phenyl radicals (optionally with substituents)both in position 1 and position 3 on the oxindole ring.

The object of the present invention is to provide additional compoundsfor the treatment or prophylaxis of various vasopressin-dependent oroxytocin-dependent diseases which have high activity.

The object has been achieved by a compound of the formula (I)

in which

-   A is an aromatic heteromonocyclic, or an aromatic or partially    aromatic heterobicyclic ring,    -   where the heterocycles are 5- or 6-membered rings and comprise        up to 4 heteroatoms selected from the group consisting of N, O        and S, and up to 2 oxo groups, where not more than one of the        heteroatoms is an oxygen atom,    -   and A may be substituted by radicals R¹¹, R¹² and/or R¹³,    -   where    -   R¹¹, R¹² and R¹³ at each occurrence are selected independently        of one another from the group consisting of hydrogen, chlorine,        bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH,        O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, phenyl,        C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl)        and N(C₁-C₄-alkyl)₂,-   R³ and R⁴ are selected independently of one another from the group    consisting of hydrogen, chlorine, bromine, iodine, fluorine, CN,    CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl,    phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂,    NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂, or-   R³ and R⁴ are connected to give —CH═CH—CH═CH—, —(CH₂)₄— or —(CH₂)₃—,-   R⁵ is a radical (W)—(X)—(Y)—Z, where    -   W is selected from the group consisting of C₁-C₄-alkylen,        C₂-C₄-alkenylen, C₂-C₄-alkynylen, 0, O—(C₁-C₄-alkylen), S,        S—(C₁-C₄-alkylen), NR⁵⁴, NR⁵⁴—(C₁-C₄-alkylen) and a bond,    -   X is selected from the group consisting of CO, CO—O, SO₂, NR⁵⁴,        NR⁵⁴—CO, NR⁵⁴—SO₂, CO—NR⁵⁸ and a bond,    -   Y is C₁-C₆-alkylen, C₂-C₆-alkenylen, C₂-C₆-alkynylen, or a bond,    -   Z is selected from the group consisting of hydrogen, E, O—R⁵²,        NR⁵¹R⁵², S—R⁵², where E is an unsaturated, saturated or        partially unsaturated mono-, bi- or tricyclic ring having a        maximum of 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2        oxygen atoms and/or 0 to 2 sulfur atoms, said ring may comprise        up to two oxo groups, and may be substituted by radicals R⁵⁵,        R⁵⁶, R⁵⁷, and/or up to three radicals R⁵³,    -   R⁵¹ at each occurrence is independently selected from the group        consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, phenyl and C₁-C₄-alkylen-phenyl, where the phenyl        ring may be substituted by up to two radicals R⁵³,    -   R⁵² at each occurrence is independently selected from the group        consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, E and C₁-C₄-alkylen-E,    -   R⁵³ at each occurrence is independently selected from the group        consisting of hydrogen, chlorine, bromine, iodine, fluorine, CN,        CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,    -   R⁵⁴ at each occurrence is independently selected from the group        consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, phenyl and C₁-C₄-alkylen-phenyl, where the phenyl        ring may be substituted by up to two radicals R⁵⁹,    -   R⁵⁵ at each occurrence is independently selected from the group        consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, phenyl, C₁-C₄-alkylen-phenyl, where the ring may        be substituted by up to two radicals R⁶⁰, and OH, O—C₁-C₄-alkyl,        O-phenyl, O—C₁-C₄-alkylen-phenyl, NH₂, NH(C₁-C₄-alkyl) and        N(C₁-C₄-alkyl)₂,    -   R₅₆ at each occurrence is independently a group Q¹-Q²-Q³, where    -   Q¹ is selected from the group consisting of a bond,        C₁-C₄-alkylen, C₂-C₄-alkenylen, C₂-C₄-alkynylen,        C₁-C₄-alkylen-N(C₁-C₄-alkyl), N(C₁-C₄-alkyl), C₁-C₄-alkylen-NH,        NH, N(C₁-C₄-alkyl)-C₁-C₄-alkylen, NH—C₁-C₄-alkylen, O,        C₁-C₄-alkylen-O, O—C₁-C₄-alkylen, CO—NH, CO—N(C₁-C₄-alkyl),        NH—CO, N(C₁-C₄-alkyl)-CO, CO, SO₂, SO, S, O, SO₂—NH,        SO₂—N(C₁-C₄-alkyl), NH—SO₂, N(C₁-C₄-alkyl)-SO₂, O—CO—NH,        O—CO—N(C₁-C₄-alkyl), NH—CO—O, N(C₁-C₄-alkyl)-CO—O,        N(C₁-C₄-alkyl)-CO—N(C₁-C₄-alkyl), NH—CO—N(C₁-C₄-alkyl),        N(C₁-C₄-alkyl)-CO—NH, and NH—CO—NH,    -   Q² is selected from the group consisting of C₁-C₄-alkylen,        C₂-C₄-alkenylen, C₂-C₄-alkynylen, and a bond,    -   Q³ is a hydrogen or an unsaturated, saturated or partially        unsaturated mono-, bi- or tricyclic ring having a maximum of 14        carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms        and/or 0 to 2 sulfur atoms, which may comprise up to two oxo        groups and may be substituted by the radicals R⁶³, R⁶⁴ and/or        R⁶⁵,    -   R⁵⁷ at each occurrence is independently selected from the group        consisting of hydrogen, C₁-C₆-alkyl, phenyl,        C₁-C₄-alkylen-phenyl, COOH, CO—O—C₁-C₄-alkyl, CONH₂,        CO—NH—C₁-C₄-alkyl, CO—N(C₁-C₄-alkyl)₂, CO—C₁-C₄-alkyl, CH₂—NH₂,        CH₂—NH—C₁-C₄-alkyl and CH₂—N(C₁-C₄-alkyl)₂,    -   R⁵⁸ at each occurrence is independently selected from the group        consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, phenyl and C₁-C₄-alkylen-phenyl, where the phenyl        ring may be substituted by up to two radicals R⁶²,    -   R⁵⁹, R⁶⁰ and R⁶² at each occurrence are selected independently        of one another from the group consisting of hydrogen, chlorine,        bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH,        O—C₁-C₄-alkyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂,        NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,    -   R⁶³, R⁶⁴ and R⁶⁵ at each occurrence are selected independently        of one another from the group consisting of hydrogen, chlorine,        bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH,        O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, phenyl,        C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl)        and N(C₁-C₄-alkyl)₂,-   R⁶ and R⁷ are selected independently of one another from the group    consisting of hydrogen, chlorine, bromine, iodine, fluorine, CN,    CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl,    phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂,    NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,    and their tautomeric forms, enantiomeric and diastereomeric forms,    and prodrugs thereof.

Ring A is preferably selected from the group consisting of aromaticheteromonocyclic and aromatic heterobicyclic systems comprising 1 or 2heteroatoms, where one of the 2 heteroatoms is nitrogen, more preferablyfrom benzothiazole, pyrimidine, pyridine, pyridazine, pyrazine,isoquinoline, quinoline, thiazole, benzimidazole, imidazole,benzoxazole, benzothiophene, thiophene, benzofuran and furan.

In a more preferred embodiment ring A is selected from the groupconsisting of pyridine, pyrimidine, pyrazine, thiophene, benzofuran andbenzothiazole.

In a further preferred embodiment of the compound of formula (I), R¹¹and R¹² are selected independently of one another from the groupconsisting of fluorine, chlorine, OH, O—C₁-C₄-alkyl and C₁-C₄-alkyl.More preferably, R¹¹ and/or R¹² are independently of one another methyl,methoxy or ethoxy.

Examples of ring A, substituted by R¹¹ and/or R¹², in the compound offormula (I) are 2-methoxypyridine-3-yl, 2-ethoxypyridine-3-yl,2-hydroxypyridine-3-yl, 2,4-dimethoxypyrimidine-5-yl,2,6-dimethoxypyridine-3-yl, 3-methoxypyridine-2-yl,3-methoxypyridine-4-yl, 4-methoxypyridine-3-yl, 3-methoxypyrazine-2-yl,3-methylthiophen-2-yl, 3-methylpyridin-2-yl, pyridin-2-yl or6-chlor-2-methoxypyridin-3-yl, preferably 2-methoxypyridine-3-yl,2-ethoxypyridine-3-yl, 2,4-dimethoxy-pyrimidine-5-yl or2,6-dimethoxypyridine-3-yl, and more preferably 2-methoxypyridine-3-yl.

In case of R¹¹ or R¹² being OH, the resultant substituted ring A maypredominantly be present in form of its tautomer like, for example,1,2-dihydro-2-oxopyridine-3-yl.

In a further preferred embodiment of the compounds of formulae (I) R⁶and R⁷ are independently of one another hydrogen, fluorine, chlorine,bromine, iodine, C₁-C₄-alkyl, O—C₁-C₄-alkyl, CN, CF₃ or OCF₃, preferablyhydrogen, fluorine, chlorine, methyl, methoxy, ethoxy or CN.

Furthermore, for the compounds of formula (I) R⁶ is preferably hydrogen,methoxy, methyl, F, CI or CN and/or R⁷ is preferably hydrogen, methoxy,methyl, F or CI.

The present application additionally relates to a compound of theformula (II)

in which

-   B is selected from the group consisting of thiophene, furan,    pyrrole, pyridine, quinoline, tetrahydroquinoline, isoquinoline,    tetrahydroisoquinoline, benzothiophene, benzofuran,    dihydrobenzofuran, indole, dihydroisoindole,    an aromatic heteromonocyclic and an aromatic or partially aromatic    heterobicyclic ring,    -   where the heterocycles are 5- or 6-membered rings and comprise 2        to 4 heteroatoms selected from the group consisting of N, O and        S, and up to 2 oxo groups, and    -   B may be substituted by the radicals R²¹, R²² and/or R²³,    -   R²¹, R²² and R²³ at each occurrence are selected independently        of one another from the group consisting of hydrogen, chlorine,        bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH,        O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, phenyl,        C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl)        and N(C₁-C₄-alkyl)₂, morpholin-4-yl, pyrrolidin-1-yl,        piperidin-1-yl, 4-piperazin-1-yl,        4-(C₁-C₄-alkyl)-piperazin-1-yl,-   R³ and R⁴ and selected independently of one another from the group    consisting of hydrogen, chlorine, bromine, iodine, fluorine, CN,    CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl,    phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂,    NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂, or-   R³ and R⁴ are connected to give —CH═CH—CH═CH—, —(CH₂)₄— or —(CH₂)₃—,-   R⁵ is a radical (W)—(X)—(Y)—Z, where    -   W is selected from the group consisting of C₁-C₄-alkylen,        C₂-C₄-alkenylen, C₂-C₄-alkynylen, 0, O—(C₁-C₄-alkylen), S,        S—(C₁-C₄-alkylen), NR⁵⁴, NR⁵⁴—(C₁-C₄-alkylen) and a bond,

X is selected from the group consisting of CO, CO—O, SO₂, NR⁵⁴, NR⁵⁴—CO,NR⁵⁴—SO₂, CO—NR⁵⁸ and a bond,

-   -   Y is C₁-C₆-alkylen, C₂-C₆-alkenylen, C₂-C₆-alkynylen, or a bond,    -   Z is selected from the group consisting of hydrogen, E, O—R⁵²,        NR⁵¹R⁵², S—R⁵², where    -   E is an unsaturated, saturated or partially unsaturated mono-,        bi- or tricyclic ring having a maximum of 14 carbon atoms and 0        to 5 nitrogen atoms, 0 to 2 oxygen atoms and/or 0 to 2 sulfur        atoms, said ring may comprise up to two oxo groups, and may be        substituted by radicals R⁵⁵, R⁵⁶, R⁵⁷ and/or up to three        radicals R⁵³ and,    -   R⁵¹ at each occurrence is independently selected from the group        consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, phenyl and C₁-C₄-alkylen-phenyl, where the phenyl        ring may be substituted by up to two radicals R⁵³,    -   R⁵² at each occurrence is independently selected from the group        consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, E and C₁-C₄-alkylen-E,    -   R⁵³ at each occurrence is independently selected from the group        consisting of hydrogen, chlorine, bromine, iodine, fluorine, CN,        CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,    -   R⁵⁴ at each occurrence is independently selected from the group        consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, phenyl and C₁-C₄-alkylen-phenyl, where the phenyl        ring may be substituted by up to two radicals R⁵⁹,    -   R⁵⁵ at each occurrence is independently selected from the group        consisting of C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl,        C₁-C₄-alkylen-phenyl, where the ring may be substituted by up to        two radicals R⁶⁰, and OH, O—C₁-C₄-alkyl, O-phenyl,        O—C₁-C₄-alkylen-phenyl, NH₂, NH(C₁-C₄-alkyl) and        N(C₁-C₄-alkyl)₂,    -   R⁵⁶ is a group Q′-Q²-Q³, where    -   Q¹ is selected from the group consisting of a bond,        C₁-C₄-alkylen, C₂-C₄-alkenylen, C₂-C₄-alkynylen, N(C₁-C₄-alkyl),        C₁-C₄-alkylen-NH, NH, N(C₁-C₄-alkyl)-C₁-C₄-alkylen,        NH—C₁-C₄-alkylen, O, C₁-C₄-alkylen-O, O—C₁-C₄-alkylen, CO—NH,        CO—N(C₁-C₄alkyl), NH—CO, N(C₁-C₄-alkyl)-CO, CO, SO₂, SO, S, O,        SO₂—NH, SO₂—N(C₁-C₄-alkyl), NH—SO₂, N(C₁-C₄-alkyl)-SO₂, O—CO—NH,        O—CO—N(C₁-C₄-alkyl), NH—CO—O, N(C₁-C₄-alkyl)-CO—O,        N(C₁-C₄-alkyl)-CO—N(C₁-C₄-alkyl), NH—CO—N(C₁-C₄-alkyl),        N(C₁-C₄-alkyl)-CO—NH, and NH—CO—NH,    -   Q² is selected from the group consisting of C₁-C₄-alkylen,        C₂-C₄-alkenylen, C₂-C₄-alkynylen, and a bond,    -   Q³ is a hydrogen or an unsaturated, saturated or partially        unsaturated mono-, bi- or tricyclic ring having a maximum of 14        carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms        and/or 0 to 2 sulfur atoms, which may comprise up to two oxo        groups and may be substituted by the radicals R⁶³, R⁶⁴ and/or        R⁶⁵,    -   R⁵⁷ at each occurrence is independently selected from the group        consisting of hydrogen, C₁-C₆-alkyl, phenyl,        C₁-C₄-alkylen-phenyl, COOH, CO—O—C₁-C₄-alkyl, CONH₂,        CO—NH—C₁-C₄-alkyl, CO—N(C₁-C₄-alkyl)₂, CO—C₁-C₄-alkyl, CH₂—NH₂,        CH₂—NH—C₁-C₄-alkyl and CH₂—N(C₁-C₄-alkyl)₂,    -   R⁵⁸ at each occurrence is independently selected from the group        consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, phenyl and C₁-C₄-alkylen-phenyl, where the phenyl        ring may be substituted by up to two radicals R⁶²,    -   R⁵⁹, R⁶⁰ and R⁶² at each occurrence are selected independently        of one another from the group consisting of hydrogen, chlorine,        bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH,        O—C₁-C₄-alkyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂,        NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,    -   R⁶³, R⁶⁴ and R⁶⁵ at each occurrence are selected independently        of one another from the group consisting of hydrogen, chlorine,        bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH,        O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, phenyl,        C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl)        and N(C₁-C₄-alkyl)₂.

-   R⁶ and R⁷ are selected independently of one another from the group    consisting of hydrogen, chlorine, bromine, iodine, fluorine, CN,    CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl,    phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂,    NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,    and their tautomeric forms, enantiomeric and diastereomeric forms,    and prodrugs thereof.

Ring B is preferably selected from the group consisting of thiophene,furan, pyrrole, pyrazole, isoxazole, pyridine, pyrimidine, quinoline,isoquinoline, tetrahydroisoquinoline, benzothiophene, benzofuran,indole, imidazole, thiazole, imidazothiazole, benzooxazine andquinoxaline.

In a more preferred embodiment ring B is selected from the groupconsisting of pyridine, imidazole, thiophene, benzothiophene andquinoline.

Even more preferably, ring B is selected from

In a further preferred embodiment of the compound of formula (II), R²¹and R²² are selected independently of one another from the groupconsisting of hydrogen, chlorine, bromine, C₁-C₄-alkyl andO—C₁-C₄-alkyl. Particularly, R²¹ and R²² are independently of oneanother hydrogen, chlorine, bromine, methyl or methoxy.

In further particularly preferred embodiments, B is

wherein

-   -   R²¹ is selected from methyl, methoxy, chlorine or bromine, and    -   R²² is methyl.

In a further preferred embodiment of the compounds of formula (II) R⁶and R⁷ are independently of one another hydrogen, fluorine, chlorine,bromine, iodine, C₁-C₄-alkyl, O—C₁-C₄-alkyl, CF₃ or OCF₃, preferablyhydrogen, fluorine, chlorine, methyl, ethyl, propyl, i-propyl, methoxy,ethoxy, propoxy, i-propoxy.

For the compounds of formula (II) R⁶ is preferably hydrogen, methoxy,ethoxy, propoxy, i-propoxy, methyl, ethyl, fluorine or chlorine, mostpreferably methoxy or ethoxy. Further, R⁶ is more preferably in position2 of the phenyl ring.

For the compounds of formula (II), R⁷ is preferably hydrogen, methoxy, For CI, most preferably hydrogen.

The present invention additionally relates to a compound of the formula(III),

in which

-   D is an aromatic heteromonocyclic, or an aromatic or partially    aromatic heterobicyclic ring,    -   where the heterocycles are 5- or 6-membered rings and comprise        up to 4 heteroatoms selected from the group consisting of N, O        and S, and up to 2 oxo groups,    -   and D may be substituted by radicals R²¹, R²² and/or R²³,-   G is an aromatic heteromonocyclic, aromatic or partially aromatic    heterobicyclic ring,    -   where the heterocycles are 5- or 6-membered rings and comprise        up to 4 heteroatoms selected from the group consisting of N, O        and S, and up to 2 oxo groups and    -   G may be substituted by radicals R⁷¹, R⁷² and/or R⁷³,    -   R²¹, R²², R²³, R⁷¹, R⁷², and R⁷³ at each occurrence are selected        independently of one another from the group consisting of        hydrogen, chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃,        —NO₂, OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl,        phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂,        NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂, morpholin-4-yl,        pyrrolidin-1-yl, piperidin-1-yl, 4-piperazin-1-yl,        4-(C₁-C₄-alkyl)-piperazin-1-yl,-   R³ and R⁴ are selected independently of one another from the group    consisting of hydrogen, chlorine, bromine, iodine, fluorine, CN,    CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl,    phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂,    NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂, or-   R³ and R⁴ are connected to give —CH═CH—CH═CH—, —(CH₂)₄— or —(CH₂)₃—,-   R⁵ is a radical (W)—(X)—(Y)—Z, where    -   W is selected from the group consisting of C₁-C₄-alkylen,        C₂-C₄-alkenylen, C₂-C₄-alkynylen, O, O—(C₁-C₄-alkylen), S,        S—(C₁-C₄-alkylen), NR⁵⁴, NR⁵⁴—(C₁-C₄-alkylen) and a bond,    -   X is selected from the group consisting of CO, CO—O, SO₂, NR⁵⁴,        NR⁵⁴—CO, NR⁵⁴—SO₂, CO—NR⁵⁸ and a bond,    -   Y is C₁-C₆-alkylen, C₂-C₆-alkenylen, C₂-C₆-alkynylen, or a bond,    -   Z is selected from the group consisting of hydrogen, E, O—R⁵²,        NR⁵¹R⁵², S—R⁵², where    -   E is an unsaturated, saturated or partially unsaturated mono-,        bi- or tricyclic ring having a maximum of 14 carbon atoms and 0        to 5 nitrogen atoms, 0 to 2 oxygen atoms and/or 0 to 2 sulfur        atoms, which may comprise up to two oxo groups, and E may be        substituted by radicals R⁵⁵, R⁵⁶, R⁵⁷ and/or up to three        radicals R⁵³,    -   R⁵¹ at each occurrence is independently selected from the group        consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, phenyl and C₁-C₄-alkylen-phenyl, where, the        phenyl ring may be substituted by up to two radicals R⁵³,    -   R⁵² at each occurrence is independently selected from the group        consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, E and C₁-C₄-alkylen-E,    -   R⁵³ at each occurrence is independently selected from the group        consisting of hydrogen, chlorine, bromine, iodine, fluorine, CN,        CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,    -   R⁵⁴ at each occurrence is independently selected from the group        consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, phenyl and C₁-C₄-alkylen-phenyl, where the phenyl        ring may be substituted by up to two radicals R⁵⁹,    -   R⁵⁵ at each occurrence is independently selected from the group        consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, phenyl, C₁-C₄-alkylen-phenyl, where the ring may        be substituted by up to two radicals R⁶⁰, and OH, O—C₁-C₄-alkyl,        O-phenyl, O—C₁-C₄-alkylen-phenyl, NH₂, NH(C₁-C₄-alkyl) and        N(C₁-C₄-alkyl)₂,    -   R⁵⁶ is a group Q¹-Q²-Q³, where    -   Q¹ is selected from the group consisting of a bond,        C₁-C₄-alkylen, C₂-C₄-alkenylen, C₂-C₄-alkynylen,        C₁-C₄-alkylen-N(C₁-C₄-alkyl), N(C₁-C₄-alkyl), C₁-C₄-alkylen-NH,        NH, N(C₁-C₄-alkyl)-C₁-C₄-alkylen, NH—C₁-C₄-alkylen, O,        C₁-C₄-alkylen-O, O—C₁-C₄-alkylen, CO—NH, CO—N(C₁-C₄-alkyl),        NH—CO, N(C₁-C₄-alkyl)-CO, CO, SO₂, SO, S, O, SO₂—NH,        SO₂—N(C₁-C₄-alkyl), NH—SO₂, N(C₁-C₄-alkyl)-SO₂, O—CO—NH,        O—CO—N(C₁-C₄-alkyl), NH—CO—O, N(C₁-C₄-alkyl)-CO—O,        N(C₁-C₄-alkyl)-CO—N(C₁-C₄-alkyl), NH—CO—N(C₁-C₄-alkyl),        N(C₁-C₄-alkyl)-CO—NH, and NH—CO—NH,    -   Q² is selected from the group consisting of C₁-C₄-alkylen,        C₂-C₄-alkenylen, C₂-C₄-alkynylen, and a bond,    -   Q³ is a hydrogen or an unsaturated, saturated or partially        unsaturated mono-, bi- or tricyclic ring having a maximum of 14        carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms        and/or 0 to 2 sulfur atoms, which may comprise up to two oxo        groups and may be substituted by the radicals R⁶³, R⁶⁴ and/or        R⁶⁵,    -   R⁵⁷ at each occurrence is independently selected from the group        consisting of C₁-C₆-alkyl, phenyl, C₁-C₄-alkylen-phenyl, COOH,        CO—O—C₁-C₄-alkyl, CONH₂, CO—NH—C₁-C₄-alkyl, CO—N(C₁-C₄-alkyl)₂,        CO—C₁-C₄-alkyl, CH₂—NH₂, CH₂—NH—C₁-C₄-alkyl and        CH₂—N(C₁-C₄-alkyl)₂,    -   R⁵⁸ at each occurrence is independently selected from the group        consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, phenyl and C₁-C₄-alkylen-phenyl, where the phenyl        ring may be substituted by up to two radicals R⁶²,    -   R⁵⁹, R⁶⁰ and R⁶² at each occurrence are selected independently        of one another from the group consisting of hydrogen, chlorine,        bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH,        O—C₁-C₄-alkyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂,        NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,    -   R⁶³, R⁶⁴ and R⁶⁵ at each occurrence are selected independently        of one another from the group consisting of hydrogen, chlorine,        bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH,        O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, phenyl,        C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl)        and N(C₁-C₄-alkyl)₂, and their tautomeric forms, enantiomeric        and diastereomeric forms, and prodrugs thereof.

Ring D is preferably selected from the group consisting of aromaticheteromonocyclic and aromatic heterobicyclic systems comprising 1 or 2heteroatoms, where one of the 2 heteroatoms is nitrogen, more preferablyfrom benzothiazole, pyrimidine, pyridine, pyridazine, pyrazine,isoquinoline, quinoline, thiazole, benzimidazole, imidazole,benzoxazole, benzothiophene, thiophene, benzofuran and furan.

In a particularly preferred embodiment ring ID is selected from thegroup consisting of pyridine, pyrimidine, pyrazine, thiophene,benzofuran and benzothiazole.

In a further preferred embodiment of the compound of formula (III) R²¹and R²² are selected independently of one another from the groupconsisting of hydroxy, fluorine, chlorine, C₁-C₄-alkyl andO—C₁-C₄-alkyl. Particularly, R²¹ and R²² are independently of oneanother hydrogen, hydroxy, chlorine, methyl, methoxy or ethoxy, mostpreferably hydrogen, methyl, methoxy or ethoxy.

Examples of ring D, substituted by R²¹ and/or R²², are2-methoxypyridine-3-yl, 2-ethoxypyridine-3-yl, 2-hydroxypyridine-3-yl,2,4-dimethoxypyrimidine-5-yl, 2,6-dimethoxypyridine-3-yl,3-methoxypyridine-2-yl, 3-methoxypyridine-4-yl, 4-methoxypyridine-3-yl,3-methoxypyrazine-2-yl, 3-methylthiophen-2-yl, 3-methylpyridin-2-yl,pyridin-2-yl or 6-chlor-2-methoxypyridin-3-yl, preferably2-methoxypyridine-3-yl, 2-ethoxypyridine-3-yl;2;4-dimethoxy-pyrimidine-5-yl or -2,6-dimethoxypyridine-3-yl, and morepreferably 2-methoxypyridine-3-yl.

In case of R²¹ or R²² being OH, the resultant substituted ring D maypredominantly be present in form of its tautomer like, for example,1,2-dihydro-2-oxopyridine-3-yl.

Ring G is preferably selected from the group consisting of thiophene,furan, pyrrole, pyrazole, isoxazole, pyridine, pyrimidine, quinoline,isoquinoline, tetrahydroisoquinoline, benzothiophene, benzofuran,indole, imidazole, thiazole, imidazothiazole, benzooxazine andquinoxaline.

In a particularly preferred embodiment ring G is selected from the groupconsisting of imidazole, pyridine, thiophene, benzothiophene andquinoline.

Even more preferably, ring G is selected from

In a further preferred embodiment R⁷¹ and R⁷² are selected independentlyof one another from the group consisting of C₁-C₄-alkyl, O—C₁-C₄-alkyl,chlorine and bromine. Particularly, R⁷¹ and

R⁷² are independently of one another methyl, methoxy, chlorine orbromine.

In a further particularly preferred embodiment ring G is

-   -   wherein        -   R⁷¹ is methyl, methoxy, chlorine or bromine, and        -   R⁷² is methyl.

In preferred embodiments of the compounds of formulae (I), (II) or(III), R³ is selected from the group consisting of hydrogen, C₁₋₄-alkyl,C₂₋₄-alkenyl, C₂₋₄-alkynyl, O—C₁₋₄-alkyl, fluorine, chlorine, bromine,iodine, CN, CF₃ and OCF₃. More preferably, R³ is selected from the groupconsisting of methyl, methoxy, fluorine, chlorine, bromine, iodine, CNand OCF₃.

Furthermore, in the compounds of formulae (I), (II) or (III) R³ ispreferably present in position 5 of the oxindole ring:

R⁴ is in the compounds of formulae (I), (II) or (III) preferablyhydrogen.

FIRST PREFERRED EMBODIMENT OF R⁵ IN THE COMPOUNDS OF FORMULAE (I), (II)OR (III)

According to this preferred embodiment, R⁵ is a radical (W)—(X)—(Y)—Z asdefined in the compounds of formulae (I), (II) or (III) wherein at leastone, preferably two, more preferably three and particularly all of W, X,Y and Z have the following definition:

-   -   W is NR⁵⁴—(C₁-C₄-alkylen);    -   X is CO;    -   Y is a bond; and/or    -   Z is E, O—R⁵² or NR⁵¹R⁵².

A preferred combination of W, X, Y and Z results in a group R⁵ havingthe following definition:

-   -   wherein        -   R⁸¹ is hydrogen or C₁-C₃-alkyl, preferably methyl,        -   R⁵² is hydrogen or C₁-C₃-alkyl, preferably hydrogen or            methyl, and R⁸¹ and R⁸² contain together up to 3 carbon            atoms,        -   E is a saturated monocyclic ring having a maximum of 8,            preferably a maximum of 6 and particularly 4 or 5 carbon            atoms and 0 to 5, preferably 1 or 2 and particularly 1            nitrogen atom, and is preferably connected to the adjacent            carbon atom of the carbonyl group via a nitrogen atom, and        -   R⁵¹, R⁵² and R⁵⁴ are as defined in the compounds of formulae            (I), (II) or (III).

Preferably one, more preferably two and most preferably all of R⁵¹, R⁵²and R⁵⁴ have the following definition:

-   -   R⁵¹ is hydrogen, C₁-C₄-alkyl, preferably methyl;    -   R⁵² is hydrogen, C₁-C₄-alkyl, preferably methyl; and/or    -   R⁵⁴ is hydrogen or C₁-C₄-alkyl, preferably hydrogen or methyl,

In a further preferred embodiment E is azetidine, piperazine,pyrrolidine, piperidine or morpholine.

Furthermore, particularly preferred are combinations of preferredembodiments of the above defined groups in the first preferredembodiment of R⁵.

SECOND PREFERRED EMBODIMENT OF R⁵ IN THE COMPOUNDS OF FORMULAE (I), (II)OR (III)

According to this preferred embodiment, R⁵ is a radical (W)—(X)—(Y)—Z asdefined in the compounds of formulae (I), (II) or (III) wherein at leastone, preferably two, more preferably three and particularly all of W, X,Y and Z have the following definition:

-   -   W is a bond;    -   X is a bond;    -   Y is a bond; and/or    -   Z is E.

Preferably, E is a saturated or partially unsaturated monocyclic ringhaving a maximum of 8, preferably a maximum of 6 and particularly 4 or 5carbon atoms, and 0 to 3, preferably 1 or 2 and particularly 1 nitrogenatom.

In a further preferred embodiment E is azetidine, piperazine,pyrrolidine or piperidine.

In a further preferred embodiment E is piperidine bonded to Z via thering nitrogen atom.

In one preferred embodiment E is unsubstituted.

In another preferred embodiment E is substituted by one or two radicalsR⁵³, with R⁵³ being defined as in the compounds of formulae (I), (II) or(III). More preferably R⁵³ is fluorine, OH, C₁-C₄-alkyl, O—C₁-C₄-alkylor CN, more preferably fluorine, OH, methyl or methoxy and mostpreferably fluorine or OH. In a further preferred embodiment E issubstituted by two radicals R⁵³ in geminal position, particularly withR⁵³ being fluorine.

In a further preferred embodiment E is substituted by one radical R⁵⁵ asdefined in the compounds of formulae (I), (II) or (III). More preferablyR⁵⁵ is phenyl, O-phenyl or O-benzyl.

Furthermore, E is preferably substituted by one radical R⁵⁶ as definedin the compounds of formulae (I), (II) or (III) wherein at least one,preferably two and particularly all of Q¹, Q² and Q³ have the followingdefinition:

-   -   Q¹ is CO,    -   Q² is a bond, and/or    -   Q³ is a saturated or partially unsaturated monocyclic ring        having a maximum of 8, preferably a maximum of 6 and        particularly 4 or 5 carbon atoms and 0 to 5, preferably 1 or 2        and particularly 1 nitrogen atom and is preferably connected to        Q² via a nitrogen atom.

In a further preferred embodiment Q³ is azetidine, piperazine,pyrrolidine, piperidine or morpholine.

Moreover, E is preferably substituted by one radical R⁵⁷ as defined inthe compounds of formulae (I), (II) or (III). More preferably R⁵⁷ isCO—N(C₁-C₄-alky)₂ or CO—O—C₁-C₄-alkyl, and in particular CO—N(CH₃)₂.

Preferred combinations of W, X, Y, Z, R⁵³, R⁵⁵ and/or R⁵⁷ result ingroups R⁵ having the following definition:

wherein

-   -   x is 1 or 2.

More preferred combinations of W, X, Y, Z, R⁵³ and/or R⁵⁷ result ingroups R⁵ having the following definition:

Particularly preferred combinations of W, X, Y, Z, R⁵³ and/or R⁵⁷ resultin groups R⁵ having the following definition:

Furthermore, particularly preferred are combinations of preferredembodiments of the above defined groups in the second preferredembodiment of R⁵.

In a further preferred embodiment a compound of the formula (I), (II) or(III) is disclosed, wherein E is pyrrolidine bonded to Z via the ringnitrogen atom, with R⁵³ at position C-4 and selected from the groupconsisting of fluorine, OH, C₁-C₄-alkyl, O—C₁-C₄-alkyl or CN, and withR⁵⁶ at position C-2 selected from the group consisting of hydrogen,C₁-C₄-alkyl, phenyl, C₁-C₄-alkylen-phenyl, COOH, CO—O—C₁-C₄-alkyl,CONH₂, CO—NH—C₁-C₄-alkyl, CO—N(C₁-C₄-alkyl)₂, CO—C₁-C₄-alkyl, CH₂—NH₂,CH₂—NH—C₁-C₄-alkyl and CH₂—N(C₁-C₄-alkyl)₂.

THIRD PREFERRED EMBODIMENT OF R⁵ IN THE COMPOUNDS OF FORMULAE (I), (II)OR (III)

According to this preferred embodiment, R⁵ is a radical (W)—(X)—(Y)—Z asdefined in the compounds of formulae (I), (II) or (III) wherein at leastone, preferably two, more preferably three and particularly all of W, X,Y and Z have the following definition:

-   -   W is O, CH₂, NR⁵⁴ or NR⁵⁴(C₁-C₄-alkylen), preferably O or NH;    -   X is CO;    -   Y is a bond; and/or    -   Z is E.

Preferably, E is a saturated or partially unsaturated monocyclic ringhaving a maximum of 8, preferably a maximum of 6 and particularly 4 or 5carbon atoms, and 0 to 3, preferably 1 or 2 nitrogen atoms.

More preferably E is selected from the group consisting of

even more preferably from the group consisting of

and most preferably E is

wherein one bond ‘—*’ defines the bonding position to group Y and thesecond bond ‘—*’ defines the bonding position to an optional substituentR⁵⁶.

Further, according to one embodiment E is

Moreover, according to another embodiment E is

Preferably, E is substituted by R⁵⁶ as defined in compounds of formulae(I), (II) or (III), wherein at least one, preferably two andparticularly all of Q¹, Q² and Q³ have the following definition:

-   -   Q¹ is a bond,    -   Q² is a bond,    -   Q³ is a unsaturated, saturated or partially unsaturated        monocyclic ring having a maximum of 8, preferably 6 and        particularly 4 or 5 carbon atoms, 0 to 5 and preferably 1 or 2        nitrogen atoms, 0 to 2 and preferably 0 or 1 oxygen atoms, and 0        to 2 and preferably 0 or 1 sulfur atom.

Preferably, Q³ is substituted by R⁶³ as defined in compounds of formulae(I), (II) or (III). R⁶³ is preferably C₁-C₄-alkyl and particularlymethyl.

More preferably, Q³ is selected from the group consisting of

and even more preferably from the group consisting of

Still more preferably Q³ is

According to one embodiment Q³ is

According to another embodiment Q³ is

Particularly preferred are combinations of W, X, Y, Z and R⁶³ resultingin the following groups R⁵:

Furthermore, particularly preferred are combinations of preferredembodiments of the above defined groups in the third preferredembodiment of R⁵.

Particularly preferred are compounds of formula (I) wherein at least twoand most preferably all of A, R³, R⁴, R⁵, R⁶ and R⁷ are definedaccording to above described preferred embodiments of these groups.

Particularly preferred are further compounds of formula (II) wherein atleast two and most preferably all of B, R³, R⁴, R⁵, R⁶ and R⁷ aredefined according to above described preferred embodiments of thesegroups.

Particularly preferred are moreover compounds of formula (III) whereinat least two and most preferably all of A, R³, R⁴, R⁵, R⁶ and R⁷ aredefined according to above described preferred embodiments of thesegroups.

The terms “alkyl”, “alkylene”, “alkenyl”, “alkenylene”, “alkynyl” and“alkynylene” as used herein always include unbranched or branched“alkyl”, “alkylene”, “alkenyl”, “alkenylene”, “alkynyl” or “alkynylene”.

C₁-C₄-alkyl as used herein is preferably methyl, ethyl, n-propyl,i-propyl, n-butyl, sec-butyl or t-butyl.

C₁-C₄-alkylene as used herein is preferably methylene, ethylene, orbranched or unbranched propylene or butylene.

C₂-C₄-alkenyl as used herein is preferably ethenyl, or branched orunbranched propenyl or butenyl.

C₂-C₄-alkenylene as used herein is preferably ethenylene, or branched orunbranched propenylene or butenylene.

C₂-C₄-alkynyl as used herein is preferably ethynyl, or branched orunbranched propynyl or butynyl.

C₂-C₄-alkynylene as used herein is preferably ethynylene, or branched orunbranched propynylene or butynylene.

C₁-C₆-alkyl as used herein is preferably branched or unbranched hexyl orpentyl, more preferably C₁-C₄-alkyl, and in particular methyl, ethyl,n-propyl, i-propyl, n-butyl, sec-butyl or t-butyl.

C₁-C₆-alkylene as used herein is preferably branched or unbranchedhexylene or pentylene, more preferably C₁-C₄-alkylene, and in particularmethylene, ethylene, or branched or unbranched propylene or butylene.

C₂-C₆-alkenyl as used herein is preferably branched or unbranchedhexenyl or pentenyl, more preferably C₂-C₄-alkenyl, and in particularethenyl, or branched or unbranched propenyl or butenyl.

C₂-C₆-alkenylene as used herein is preferably branched or unbranchedhexenylene or pentenylene, more preferably C₂-C₄-alkenylene, and inparticular ethenylene, or branched or unbranched propenylene orbutenylene.

C₂-C₆-alkynyl as used herein is preferably branched or unbranchedhexynyl or pentynyl, more preferably C₂-C₄-alkynyl, and in particularethynyl, or branched or unbranched propynyl or butynyl.

C₂-C₆-alkynylene as used herein is preferably branched or unbranchedhexynylene or pentynylene, more preferably C₂-C₄-alkynylene, and inparticular ethynylene, or branched or unbranched propynylene orbutynylene.

As used herein, “benzothiazole” means 2-, 3-, 4-, 5-, 6- or7-benzothiazole, “pyrimidine” means 2-, 4-, 5-, or 6-pyrimidine,“pyridine” means 2-, 3-, 4-, 5- or 6-pyridine, “pyridazine” means 3-,4-, 5- or 6-pyridazine, “pyrazine” means 2-, 3-, 5- or 6-pyrazine,“isoquinoline” means 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinoline,“quinoline” means 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinoline, “thiazole”means 2-, 4- or 5-thiazole, “benzimidazole” means 2-, 4-, 5-, 6- or7-benzimidazole, “imidazole” means 2-, 4- or 5-imidazole, “benzoxazole”means 2-, 4-, 5-, 6- or 7-benzoxazole, “benzothiophene” means 2-, 3-,4-, 5-, 6-, or 7-benzothiophene, “thiophene” means 2-, 3-, 4- or5-thiophene, “benzofuran” means 2-, 3-, 4-, 5-, 6- or 7-benzofuran and“furan” means 2-, 3-, 4- or 5-furan.

Further, as used herein, “pyrrole” means 2-, 3-, 4- or 5-pyrrole,“tetrahydroquinoline” means 1-, 2-, 3-, 4-, 5-, 6-, 7- or8-tetrahydroquinoline, “tetrahydroisoquinoline” means 1-, 2-, 3-, 4-,5-, 6-, 7- or 8-tetrahydroisoquinoline, “dihydrobenzofuran” means 2-,3-, 4-, 5-, 6- or 7-dihydrobenzofuran, “indole” means 1-, 2-, 3-, 4-,5-, 6- or 7-indole, “dihydroisoindole” means 1-, 2-, 3-, 4-, 5-, 6- or7-dihydroisoindole.

Further, as used herein, “pyrazole” means 1-, 3-, 4- or 5-pyrazole,“isoxazole” means 3-, 4- or 5-isoxazole, “imidazothiazole” means 2-, 4-,5- or 6-imidazothiazole, “benzoxazine” means 2-, 3-, 4-, 5-, 6-, 7- or8-benzoxazine, “quinoxaline” means 2-, 3-, 5-, 6-, 7- or 8-quinoxaline.

Further, as used herein, “azetidine” means 1-, 2-, 3- or 4-azetidine,“piperazine” means 1-, 2-, 3-, 4-, 5- or 6-piperazine, “pyrrolidine”means 1-, 2-, 3-, 4- or 5-pyrrolidine, “piperidine” means 1-, 2-, 3-,4-, 5- or 6-piperidine and “morpholine” means 2-, 3-, 4-, 5- or6-morpholine.

At each occurrence in the present application, the formulations “NR⁵⁴”and CO—NR⁵⁸ shall, particularly in a preferred embodiment, include NHR⁵⁴and CO—NHR⁵⁸, respectively.

At each occurrence in the present application, the formulation“N(definition of residue)_(number)” (e.g., “N(C₁-C₄-alkyl)₂”) shall,particularly in a preferred embodiment, be understood that each of theresidues according to the given “number” may have independently of eachother either the same or different meanings. For example,“N(C₁-C₄-alkyl)₂” shall represent “N(C₁-C₄-alkyl)(C₁-C₄-alkyl)” whereinboth residues “(C₁-C₄-alkyl)” are each bonded to the nitrogen atom andmay have either the same or different meanings.

At each occurrence in the present application, the formulation “E is anunsaturated, saturated or partially unsaturated mono-, bi- or tricyclicring having a maximum of 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to2 oxygen atoms and/or 0 to 2 sulfur atoms, said ring may comprise up totwo oxo groups, and may be substituted by radicals R⁵⁵, R⁵⁶, R⁵⁷, and/orup to three radicals R⁵³” shall, particularly as a preferred embodiment,have the meaning of “E is an unsaturated, saturated or partiallyunsaturated mono-, bi- or tricyclic ring having as ring members any offrom 2 to (a maximum of) 14 carbon atoms and any of 0, 1, 2, 3, 4 and 5nitrogen atoms, any of 0, 1 and 2 oxygen atoms and any of 0, 1 and 2sulfur atoms, said ring comprising any of 0, 1 and 2 oxo groups and beoptionally substituted at the ring carbon atom and/or ring nitrogen atomby from one to three radicals selected from the group consisting of R⁵⁵,R⁵⁶ and R⁵⁷, and with 1, 2 or 3 radicals R⁵³ which independently of eachother may have either identical or different meanings, wherein E can bebonded to Y via a carbon ring atom or a nitrogen ring atom” and, morepreferably, the meaning of “E is an unsaturated, saturated or partiallyunsaturated mono-, bi- or tricyclic ring having as ring members 2, 3, 4;5, 6, 7, 8, 9, 10, 11, 12, 13 or a maximum of 14 carbon atoms and 0, 1,2, 3, 4 or 5 nitrogen atoms, 0, 1 or 2 oxygen atoms and/or 0, 1 or 2sulfur atoms, said ring comprise 0, 1 or 2 oxo groups and be optionallysubstituted at the ring carbon atom and/or ring nitrogen atom byradicals R⁵⁵, R⁵⁶ and/or R⁵⁷, and/or with 1, 2 or 3 radicals R⁵³ whichindependently of each other may have either identical or differentmeanings, wherein E can be bonded to Y via a carbon ring atom or anitrogen ring atom”.

At each occurrence in the present application, the formulation “Q³ is ahydrogen or an unsaturated, saturated or partially unsaturated mono-,bi- or tricyclic ring having as ring members a maximum of 14 carbonatoms and 0 to 5 nitrogen atoms, 0 to 2 oxygen atoms and/or 0 to 2sulfur atoms, which may comprise up to two oxo groups and may besubstituted by the radicals R⁶³, R⁶⁴ and/or R⁶⁵” shall have,particularly as a preferred embodiment, the meaning of “Q³ is a hydrogenor an unsaturated, saturated or partially unsaturated mono-, bi- ortricyclic ring having as ring members any from 2 to (a maximum of) 14carbon atoms and any of 0, 1, 2, 3, 4 and 5 nitrogen atoms, and any of0, 1 and 2 oxygen atoms and any of 0, 1 and 2 sulfur atoms, said ringmay comprise any of 0, 1 and 2 oxo groups and may be substituted at thecarbon ring atom and/or the nitrogen ring atom by the radicals R⁶³, R⁶⁴and/or R⁶⁵ which independently of each other may have either identicalor different meanings, wherein Q³ can be bonded to Q² via a Carbon ringatom or a nitrogen ring atom” and, more preferably, the meaning of “Q³is a hydrogen or an unsaturated, saturated or partially unsaturatedmono-, bi- or tricyclic ring having as ring members any of from 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13 and 14 carbon atoms and any of 0, 1, 2, 3,4 and 5 nitrogen atoms, and any of 0, 1 and 2 oxygen atoms and any of 0,1 and 2 sulfur atoms, said ring may comprise any of 0, 1 and 2 oxogroups and may be substituted at the carbon ring atom and/or nitrogenring atom by the radicals R⁶³, R⁶⁴ and/or R⁶⁵ which independently ofeach other may have either identical or different meanings, wherein Q³can be bonded to Q² via a carbon ring atom or a nitrogen ring atom”.

At each occurrence in the present application, the formulation “wherethe heterocycles are 5- or 6-membered rings and comprise up to 4heteroatoms selected from the group consisting of N, O and S, and up to2 oxo groups, where not more than one of the heteroatoms is an oxygenatom” shall have, particularly as a preferred embodiment, the meaning of“where the heterocycles as forming part of the heteromonocyclic orheterobicyclic ring are 5- or 6-membered rings and per heteromonocyclicor heterobicyclic ring may comprise any of 1, 2, 3 and 4 heteroatomswhich independently of each other are selected from the group consistingof N, O and S, said heterocycles may further comprise any of 0, 1 and 2oxo groups, whereby not more than one of the heteroatoms is an oxygenatom”.

At each occurrence in the present application, the formulation “wherethe heterocycles are 5- or 6-membered rings and comprise 2 to 4heteroatoms selected from the group consisting of N, O and S, and up to2 oxo groups” shall have, particularly as a preferred embodiment, themeaning of “where the heterocycles as forming part of theheteromonocyclic or heterobicyclic ring are 5- or 6-membered rings andper heteromonocyclic or heterobicyclic ring may comprise any of 2, 3 and4 heteroatoms which independently of each other are selected from thegroup consisting of N, O and S, said heterocycles may further compriseany of 0, 1 and 2 oxo groups”.

At each occurrence in the present application, the formulation “wherethe heterocycles are 5- or 6-membered rings and comprise up to 4heteroatoms selected from the group consisting of N, O and S, and up to2 oxo groups” shall have, particularly as a preferred embodiment, themeaning of “where the heterocycles as forming part of theheteromonocyclic or heterobicyclic ring are 5- or 6-membered rings andper heteromonocyclic or heterobicyclic ring may comprise any of 1, 2, 3and 4 heteroatoms which independently of each other are selected fromthe group consisting of N, O and S, said heterocycles may furthercomprise any of 0, 1 and 2 oxo groups”.

At each occurrence in the present application, in a preferred embodimentthe residue R³ is placed at position C-5 of the 1,3-dihydroindol-2-oneand selected from the group consisting of hydrogen, chlorine, bromine,iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl,O—C₁-C₄-alkylen-phenyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂ and R₄ ishydrogen.

The formulation “partially aromatic” as used herein means an aromaticsystem comprising two or more double bonds wherein at least one of saiddouble bonds has been hydrogenated by addition of hydrogen, whereby theremaining one or more double bounds may be either standing alone (incase of one double bound only), conjugated, partially conjugated or nolonger conjugated with each other.

The formulation the “[said] ring may comprise up to two oxo groups” asused herein means that said ring has up to two carbon atoms which areeach connected to an oxygen atom via a double bond.

Divalent radicals are to be read from the left to the right with respectto their bonds to other substructures of the molecule. Thus, for example“CO—NR⁵⁸” in the definition of X in R⁵ of the compound of formulae (I)to (IIII) is connected to W and Y as follows: (W)—CO—N(R⁵⁸)—(Y)—Z.

By prodrugs are meant those compounds which are metabolized in vivo tothe compounds of the invention. Typical examples of prodrugs aredescribed in C. G. Wermuth (ed.): The Practice of Medicinal Chemistry,Academic Press, San Diego, 1996, pp. 671-715. These include, forexample, phosphates, carbamates or amino acids, esters and others.

The invention further relates to the physiologically tolerated salts ofthe compounds of the invention which can be obtained by reacting thecompounds of the invention with a suitable acid or base. Suitable acidsand bases are listed for example in Fortschritte derArzneimittelforschung, 1966, Birkhäuser Verlag. vol. 10, pages 224-285.These include for example hydrochloric acid, citric acid, tartaric acid,lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formicacid, maleic acid, fumaric acid etc., and sodium hydroxide, lithiumhydroxide, potassium hydroxide and2-amino-2-(hydroxymethyl)-1,3-propanediol (Tris).

The invention further relates to the compound of any of general formulae(I) to (III) as therapeutic or prophylactic agent.

Furthermore, the invention relates to a medicament comprising thecompound of any of general formulae (I) to (III).

The compound of any of general formulae (I) to (III) can be used forproducing a medicament for the control and/or prophylaxis of variousvasopressin-dependent or oxytocin-dependent diseases.

The invention further relates to the use of the compound of any ofgeneral formulae (I) to (III) for the control and/or prophylaxis ofvarious vasopressin-dependent or oxytocin-dependent diseases.

A further aspect of the invention is a method for the therapeutic and/orprophylactic treatment of a mammal requiring a treatment byadministering the compound of any of formulae (I) to (III) for thetreatment of diseases.

Furthermore, the compound of any of formulae (I) to (III) can be usedfor the treatment of:

-   depressions and/or bipolar disorders such as, for example, dysthymic    disorders, subsyndromal depression, seasonal affected disorders,    premenstrual dysphoric disorders and/or psychotic disorders;-   anxiety and/or stress-related disorders such as, for example,    general anxiety disorders, panic disorders, obsessive-compulsive    disorders, post-traumatic disorders, acute stress disorders and/or    social phobia;-   memory disorders and/or Alzheimer's disease;-   psychoses and/or psychotic disorders; and/or-   Cushing's syndrome.

The compounds of the invention are effective after administration invarious ways, especially orally.

The compounds according to the present invention can be useful for thetreatment or prevention of various vasopressin-dependent orocytocin-dependent complaints, such as mental disorders. Examples ofsuch mental disorders according to the American Psychiatric AssociationDSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th ed.,1994 are attention-deficit and disruptive behavior disorders; delirium,dementia, and amnestic and other cognitive disorders; substance-relateddisorders, such as alcohol use disorders and alcohol-induced disorders;schizophrenia and other psychotic disorders, such as schizophrenia,schizophreniform disorder, schizoaffective disorder and delusionaldisorder; mood disorders; such as depressive disorders (major depressivedisorder, dysthymic disorder, seasonal affective disorder, premenstrualdysphoric disorder, depressive disorder not otherwise specified),bipolar disorder (bipolar I disorder, bipolar II disorder, cyclothymicdisorder, bipolar disorder not otherwise specified, substance-inducedmood disorder, mood disorder not otherwise specified); stress-relateddisorders, such as acute stress disorder; anxiety disorders, such aspanic disorder without agoraphobia, panic disorder with agoraphobia,agoraphobia without history of panic disorder, specific phobia, socialphobia, obsessive-compulsive disorder, posttraumatic stress disorder,acute stress disorder, generalized anxiety disorder, substance-inducedanxiety disorder; somatoform disorders, such as somatization disorder,undifferentiated somatoform disorder, conversion disorder, paindisorder; eating disorders; sleep disorders, such as primary sleepdisorders (dyssomnias, parasomnias), sleep disorders related to anothermental disorder. Furthermore, compounds according to the presentinvention can be useful for the treatment of Cushing syndrome.

The present invention also relates to pharmaceutical compositions whichcomprise an effective dose of a compound of the invention or of apharmaceutically acceptable salt thereof and suitable pharmaceuticalcarriers.

These pharmaceutical carriers are chosen according to the pharmaceuticalform and the desired mode of administration.

With the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical,intratracheal, intranasal, transdermal or rectal administration it ispossible to administer the compounds of the formula (I), (II) or (III)or, where suitable, the salts thereof to animals or humans in unitaryadministration forms, mixed with conventional pharmaceutical carriers,for the prophylaxis or treatment of the above disorders or diseases.

The suitable unitary administration forms include forms for oraladministration, such as tablets, gelatin capsules, powders, granules andsolutions or suspensions for oral intake, forms for sublingual, buccal,intratracheal or intranasal administration, aerosols, implants, formsfor subcutaneous, intramuscular or intravenous administration and formsfor rectal administration.

For topical administration, the compounds of the invention can be usedin creams, ointments or lotions.

In order to achieve the desired prophylactic or therapeutic effect, thedose of the basic active ingredient may vary between 0.01 and 50 mg perkg of bodyweight and per day.

Each unit dose may comprise from 0.05 to 5 000 mg, preferably 1 to 1 000mg, of the active ingredient in combination with a pharmaceuticalcarrier. This unit dose may be administered 1 to 5 times a day so that adaily dose of from 0.5 to 25 000 mg, preferably 1 to 5 000 mg, isadministered.

If a solid composition is prepared in the form of tablets, the mainingredient is mixed with a pharmaceutical carrier such as gelatin,starch, lactose, magnesium stearate, talc, silica or the like.

The tablets may be coated with sucrose, a cellulose derivative oranother suitable substance or treated otherwise in order to displaypersistent or delayed activity and in order to release a predeterminedamount of the basic active ingredient continuously.

A preparation in the form of gelatin capsules is obtained by mixing theactive ingredient with an extender and taking up the resulting mixturein soft or hard gelatin capsules.

A preparation in the form of a syrup or elixir or for administration inthe form of drops may comprise active ingredients together with asweetener, which is preferably calorie-free, methylparaben orpropylparaben as antiseptics, a flavoring and a suitable color.

The water-dispersible powders or granules may comprise the activeingredients mixed with dispersants or wetting agents, or suspendingagents, such as polyvinylpyrrolidones, and sweeteners or maskingflavors.

Rectal administration is achieved by using suppositories which areprepared with binders which melt at the rectal temperature, for examplecocoa butter or polyethylene glycols. Parenteral administration iseffected by using aqueous suspensions, isotonic salt solutions orsterile and injectable solutions which comprise pharmacologicallyacceptable dispersants and/or wetting agents, for example propyleneglycol or polyethylene glycol.

The basic active ingredient may also be formulated as microcapsules orliposomes, if suitable with one or more carriers or additives.

In addition to the compounds of the general formula (I) or theirpharmaceutically acceptable salts, the compositions of the invention maycomprise other basic active ingredients which may be beneficial for thetreatment of the abovementioned disorders or diseases.

The present invention thus further relates to pharmaceuticalcompositions in which a plurality of basic active ingredients arepresent together, where one of these is the compound of the invention.

The compounds of the invention were tested for their activity in thefollowing vasopressin V1b receptor binding assay.

Vasopressin V1b Receptor Binding Assay

The binding of the compounds of this invention to the vasopressin V1breceptor was determined with the following assay:

Dissolution of Compounds

Compounds were dissolved in a concentration of 10⁻² M or 10⁻³ M in DMSO.Further dilutions were performed with water.

Binding Assays

The procedure for the binding assay was based on the method of Tahara etal. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)). Assays(0.250 ml) consisted of membranes (58 μg protein) from CHO-K1 cellspermanently expressing human V1b receptors (preparation V1b-3H2,containing protease inhibitors, Roche complete Mini #1836170), 1.5 nM³H-AVP (8-Arg-vasopressin, NET 800) in incubation buffer (total binding)and different concentrations of test compound (displacement).Non-specific binding was defined with 10⁻⁶ M AVP. Assays were performedin triplicate.

Incubation buffer: 50 mM Tris, 10 mM MgCl₂, 0.1% BSA adjusted to pH 7.4with HCl.

After incubation, 60 min at room temperature, bound and free radioligandwas separated by filtration under vacuum through Whatman GF/B glassfibre mats using a Skatron cell harvester 7000.

Liquid scintillation counting was performed in beta-counters, Tricarbmodel 2000 or 2200CA (Packard). Dpm were calculated by a programme withstandardisation using a standard quench series.

Evaluation

Evaluation of binding parameters was performed by non-linear regressionanalysis with SAS. The strategy of this program is similar to theprogram LIGAND described by Munson and Rodbard (Munson PJ and Rodbard D,Analytical Biochem 107, 220-239 (1980)).

The compounds of the invention bind to the vasopressin V1b receptor. Inthe following Table 1 the binding affinity of selected examples for thevasopressin V1b receptor is shown.

TABLE 1 Binding affinity of selected examples for the vasopressin V1breceptor Binding affinity for the vasopressin V1b Example # receptor 2+++ 3 +++ 5 +++ 6 ++ 9 +++ 10 +++ 13 +++ 28 +++ 29 +++ 31 +++ 32 ++ 33++ 47 +++ 48 +++ 51 +++ 52 +++ 53 +++ 56 +++ 59 + 63 + 65 ++ 75 +++ 76+++ 82 +++ 83 +++ 103 +++ 104 +++ 105 +++ 107 +++ 113 +++ 115 +++ 122 ++123 ++ 125 +++ 126 +++ 127 +++ 130 +++ 134 +++ 136 +++ 143 +++ 145 +++154 +++ 158 +++ 165 ++ 166 ++ 168 +++ 169 ++ 170 ++ 171 +++ 172 ++ 220+++ 221 +++ 222 +++ 224 +++ 225 ++ 226 ++ 227 +++ 230 +++ 232 +++ 234+++ 236 +++ 237 +++ 238 +++ 239 +++ 240 +++ 241 ++ 242 +++ 243 +++ 245+++ 246 +++ 247 +++ 248 +++ 252 +++ 253 +++ 255 ++ 256 +++ 270 +++ 277++ 280 +++ 281 ++ 282 +++ 286 ++ 288 +++ 289 +++ + indicates bindingaffinity >500 nM ++ indicates binding affinity between 50 and 500 nM +++indicates binding affinity <50 nMFunctional Assay for the Human V_(1b) Receptor

Functional activity was determined by testing the effect of thecompounds on calcium release in CHO-K1 cells stably transfected withhuman V_(1b)) receptor. Cells were seeded into 96-well plates at 50,000cells/well and grown overnight in tissue culture medium (DMEM/Nut mixF12 Medium with Glutamax I (Invitrogen), containing 10% FCS, 100units/ml Penicillin, 100 μg/ml Streptomycine, 800 μg/ml Geneticin) at37° C. and 5% CO₂. Cells were loaded with a fluorescentcalcium-sensitive dye in the presence of 1% probenicid according to themanufacturers protocol (Ca⁺⁺-Plus-Assay Kit, Molecular Devices). Serialcompound dilutions (final concentrations 10⁻¹⁰ to 10⁻⁵ M) were added tothe cells either alone or in the presence of Arg-vasopressin (10⁻⁸M) andthe maximum calcium response was determined using a FLIPR-96 instrument(Molecular Devices). Concentration-response curves were fitted using athree-parameter logistic equation (GraphPad Prism). Kb values werecalculated from IC50 values according to Cheng & Prusoff(Kb=IC50/(1+L/EC50)).

Antidepressant Effects of Compounds of this Invention in the Rat ForcedSwim Model

The potential antidepressant effects of some examples of this inventionwere examined in the rat forced swim test. When rats are forced to swimin a cylinder from which no escape is possible they readily adopt acharacteristic immobile posture and make no further attempts to escapeexcept for small movements needed to keep floating. The immobility isconsidered to reflect a ‘depressive mood’ (Porsolt R D, LePichon M,Jalfre M (1977). Depression: a new animal model sensitive toantidepressant treatment. Nature 266, 730-732.), in which animals ceaseto struggle to escape the aversive situation. The immobility induced bythe procedure is influenced by a wide variety of antidepressants(Porsolt R D, Lenegre A, McArthur R A (1991). Pharmacological models ofdepression. In: Animal models in Psychopharmacology. B. Olivier, J. Mos,J. L. Slangen (eds) Birkhauser Verlag, Basel, pp. 137-159.) and has agood predictive validity in that it detects antidepressants withdifferent mechanisms of action. Administration of antidepressants suchas fluoxetine increases the time an animal struggles (decreases theimmobility time) when forced to swim in a confined space. Lack ofstruggling is thought to represent a state of despair.

Procedure: Male Sprague Dawley rats (Janvier) weighing 160-200 gram(n=6) were placed individually into a glass water tank (40 cm×21.5 cm)filled with tap water (25° C.) up to 18 cm. This pre-test lasted for 15min. Twenty-four hours later, animals were re-tested for 5 min in thesame water tank while the total immobility time, swimming time andclimbing time were recorded. Rats were considered immobile when theymade no further attempts to escape, except for movements necessary tokeep their heads above water (Porsolt R D, Anton G, Blavet N & Jalfre M.(1978). Behavioural despair in rats: a new model sensitive toantidepressant treatments. European Journal of Pharmacology 47,379-391). The absence of hind limb movements was recorded as immobilityusing a stopwatch by a single observer. The water in the bath waschanged after each trial. Drugs were administered via intraperitonealroute as suspensions in hydroxypropylmethylcellulose (HPMC) three timesbefore re-testing (for example 24, 4 and 0.5 hours before re-testing,depending on the test compound).

Some of the compounds of the invention, when tested in the rat forcedswim model, yielded results strongly suggestive of antidepressantactivity. The compounds of Examples 5 and 29 decreased the immobilitytime in a dose-dependent manner with an ED50 of <30 mg/kg. Incomparison, SSR149415 (Griebel et al., PNAS 99, 6370 (2002)), anantidepressant-like compound that is structurally related to somecompounds of this invention, showed an ED50 value of >30 mg/kg in ourrat forced swim model.

These data show that subtle changes, such as replacing the2-methoxy-phenyl group in SSR149415 with a 2-methoxy-pyridin-3-yl groupor replacing the 2,4-dimethoxy-benzenesulfonyl moiety with athiophene-2-sulfonyl moiety, can lead to compounds having significantlyenhanced activity in the rat forced swim model. Lower ED50 values, inturn, are likely to result in lower doses being required to obtainantidepressant effects, thus offering the possibility of an improvedtherapeutic index.

The synthesis of the compounds of the invention is described below.

The 1,3-dihydroindol-2-ones of the invention can be prepared in variousways, as outlined in synthesis Schemes 1-5.

Synthesis Scheme 1 (Terminology According to Claim 6)

The 3-hydroxy-1,3-dihydroindol-2-ones VI can be obtained by addition ofmetalated heterocycles IV to the 3-keto group of isatins V. Examples ofmetalated heterocycles which can be employed are the correspondingmagnesium and lithium compounds. The isatins V were either purchased orprepared by methods described in the literature (Advances inHeterocyclic Chemistry, A. R. Katritzky and A. J. Boulton, AcademicPress, New York, 1975, 18, 2-58; J. Brazil. Chem. Soc. 12, 273-324(2001)). The metalated heterocycles IV were prepared in various ways(see review article by G. Queguiner et al. in Advances in HeterocyclicChemistry, Vol. 52, ed. A. R. Katritzky, Academic Press, 1991, 187-304.:J. Heterocyclic Chem. 37, 615 (2000); Heterocyles 37, 2149, (1994)): (i)reaction of heteroaryl halides with magnesium affords in certain cases(for example 2-bromo-3-methylthiophene) the corresponding Grignardcompounds (M=Mg); (ii) reaction of heteroaryl bromides and iodides withalkyllithium reagents such as, for example, n-butyllithium,tert-butyllithium or mesityllithium at low temperatures affords incertain cases (for example 5-bromo-2,4-dimethoxypyrimidine) thelithiated heterocycles by halogen-lithium exchange; (iii) reaction ofsubstituted heterocycles with the aforementioned alkyllithium reagentsand lithium bases such as, for example, lithium diisopropylamide orlithium tetramethylpiperidylamide likewise affords in certain cases (forexample 2-methoxypyrazine) the lithiated heterocycles, especially whenthe hetero-aromatic system is substituted by ortho-directing groups suchas, for example, a methoxy group.

The 3-hydroxy-1,3-dihydroindol-2-ones VI were converted in the next stepinto compounds VII which bear a leaving group LG in position 3. Examplesfor LG are halides, mesylate and tosylate. Thus, for example, in thecase where LG is chlorine the intermediate VII can be prepared bytreating the tertiary alcohol VI with thionyl chloride in the presenceof a base such as, for example, pyridine. Alternatively, alcohols VI canbe activated by conversion into the mesylate using methanesulfonylchloride in the presence of a base such as, for example, triethylamine.The leaving group LG in the compounds VII can then be replaced byvarious nucleophiles R5-H, resulting in the compounds VIII which havethe radical R⁵ in position 3. For example, replacement reactions withprimary and secondary amines R5-H in the presence of a base such as, forexample, N,N-diisopropylethylamine in a solvent such as, for exampledichloromethane afford the analogous 3-amino-1,3-dihydroindol-2-onesVIII. The reaction is not confined to nitrogen nucleophiles; it is alsopossible for oxygen or sulfur nucleophiles R5-H, where appropriate afterdeprotonation with a suitable base such as, for example, sodium hydride.

Final sulfonylation by treating the compounds VIII with the sulfonylchlorides IX after deprotonation with a strong base such as, forexample, potassium tert-butoxide or sodium hydride in a solvent such as,for example, DMF affords the compounds X of the invention.

Synthesis Scheme 2 (Terminology According to Claim 6)

The 3-urethane derivatives XIII were prepared by initially reacting the3-hydroxy-1,3-dihydroindol-2-ones VI with heterocyclic sulfonylchlorides XI under the conditions already described above. Heterocyclicsulfonyl chlorides were either purchased or prepared by standard methods(see, for example, J. Med. Chem. 40, 1149 (1997); J. March, AdvancedOrganic Chemistry, 1992, 4th ed., Wiley, New York, p. 724). Thecompounds XIII of the invention were prepared in various ways startingfrom the sulfonylated compounds XII: (i) reaction with isocyanates L=C═O(L contains nitrogen); (ii) reaction with carbamoyl chlorides L-CO—CI (Lcontains nitrogen) in the presence of a base such as, for example,triethylamine; (iii) activation with phenyl chloroformate in thepresence of a base such as, for example, pyridine and subsequentreaction of the carbonate intermediate with amines L-H, whereappropriate at elevated temperature. Heteroaryl-substituted piperidines,that can be employed as amines L-H, can be prepared as described inTetrahedron Lett. 34, 5287 (1993) and Bioorg. Med. Chem. Lett. 11, 2213(2001) for 4-(4′-piperidinyl)-pyridine.

Compounds XXII of the invention bearing a functionalized nitrogen atomin position 3 (e.g., amides, sulfonamides, carbamates and ureas) wereprepared as described in synthesis Scheme 3. The3-amino-1,3-dihydroindol-2-ones XX were prepared for example by reactingcompounds VII (LG is a leaving group such as, for example, chloride ormesylate) with primary amines R⁵⁴—NH₂ in the presence of a base such as,for example, N,N-diisopropylethylamine in suitable solvents such as, forexample, dichloromethane. Treatment of compounds XX with sulfonylchlorides XI after deprotonation with a strong base such as, forexample, potassium tert-butoxide or sodium hydride in a solvent such as,for example, DMF afforded the 3-amino-1,3-dihydroindol-2-ones XXIsulfonylated in position 1. The amino derivatives XXII of the inventionwere prepared from the amines XXI by reaction with customary reagentsfor derivatizing amino groups, such as, for example, carboxylic acids,carbonyl chlorides, carboxylic anhydrides, sulfonyl chlorides,chloroformates, isocyanates, carbamoyl chlorides by the relevant methods(J. March, Advanced Organic Chemistry, 1992, 4th ed., Wiley, New York,pp. 417-421; 499; 903).

N-heteroaryl-substituted piperidine carboxylic acids, that can beemployed as coupling partner for the amines XXI, can be prepared forexample as described in J. Med. Chem. 43, 2087 (2000) for4-carboxy-N-(4-pyridyl)piperidine.

In addition, the 3-amino group in the compounds XXI can be substitutedby treatment with alkylating agents such as, for example, alkylbromides, iodides or mesylates, and by reaction with aldehydes orketones in the presence of reducing agents such as, for example, sodiumcyanoborohydride in the sense of a reductive amination (J. March,Advanced Organic Chemistry, 1992, 4th ed., Wiley, New York, p. 411;898).

Synthesis Scheme 3 (Terminology According to Claim 6)

Compounds XXVII of the invention in which X—Y—Z radicals are linked viaan alkylene bridge W to position 3 of the 1,3-dihydroindol-2-oneframework were prepared for example by alkylation of the deoxygenatedcompounds XXIII and, where appropriate, derivatized further. An examplefor the preparation of compounds of the XXVII type in which W is amethylene group and X is a carbonyl group is described in synthesisScheme 4: Deoxygenation of the 3-hydroxy-1,3-dihydroindol-2-ones VI tookplace with triethylsilane in trifluoroacetic acid. The esters XXIV wereprepared by alkylation of the 1,3-dihydroindol-2-ones XXIII with ethylbromoacetate in the presence of bases such as, for example, potassiumcarbonate and, where appropriate, potassium iodide. After hydrolysis ofthe ester function, for example by treatment with lithium hydroxide in awater/THF/methanol mixture, the acids XXV were coupled with amines H—Y—Zemploying relevant methods (J. March, Advanced Organic Chemistry, 1992,4th ed., Wiley, New York, pp. 417-421). Final sulfonylation of thecompounds XXVI with sulfonyl chlorides XI afforded the compounds XXVIIof the invention.

Synthesis Scheme 4 (Terminology According to Claim 6)

Compounds of the invention in which X—Y—Z radicals are linked via anoxygen atom (W═O) to position 3 of the 1,3-dihydroindol-2-one frameworkwere prepared for example by alkylation of the1-sulfonyl-3-hydroxy-1,3-dihydroindol-2-ones XII with alkylating agentssuch as, for example, aralkyl bromides, iodides or mesylates afterdeprotonation of the tertiary hydroxyl group with bases such as, forexample, sodium hydride.

Enantiopure compounds can be obtained for example by carrying out aconventional racemic resolution using suitable optically active acids orbases with compounds of the invention or intermediates which comprisebasic or acidic functional groups such as, for example, an amino orcarboxyl group.

EXAMPLES (2S,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid dimethylamidehydrochloride

-   A) BOP (172 g, 0.389 mol) was added in portions to a solution of    (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-pyrrolidine-2-carboxylic    acid (90 g, 0.398 mol) in dichloromethane (450 ml) and DIPEA (68 ml,    0.523 mol) at 0° C. and stirred at 0° C. for 1 hour. Then a 2 M    solution of dimethylamine in THF (800 ml, 1.6 mol) was added    dropwise at 0° C., and the mixture was stirred at room temperature    overnight. The reaction mixture was stirred into ice-water, and the    mixture was extracted several times with dichloromethane. The    collected organic phase was washed with saturated brine, dried over    magnesium sulfate and concentrated under reduced pressure.-   B) The intermediate from Step A was mixed with 500 ml of 5-6 M HCl    in isopropanol and stirred at room temperature for 4 hours. After    cooling to 0° C., the precipitate was filtered off, washed with    isopropanol and diethyl ether and dried. 37 g of the desired product    were obtained.

Example 1 and Example 2(2S,4R)-1-[3-Benzothiazol-2-yl-5-chloro-1-(2,4-dimethoxy-benzenesulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide A)3-Benzothiazol-2-yl-5-chloro-3-hydroxy-1,3-dihydroindol-2-one

A 1.6 M solution of n-butyllithium in hexane (35 ml, 56 mmol) was addeddropwise to a solution of benzothiazole (6.2 ml, 56 mmol) in THF (100ml) at −78° C. After stirring at −78° C. for 1.5 h, the solution of thelithiated benzothiazole was transferred via a needle into an ice-coldsuspension of 5-chloroisatin (3.63 g, 20 mmol) in THF (70 ml). Thereaction mixture was stirred at 0° C. for 1 h and then saturatedammonium chloride solution was added. The mixture was extracted threetimes with ethyl acetate and the combined organic layers were washedwith saturated brine. The organic phase was dried over magnesiumsulfate, filtered and concentrated under reduced pressure, during whichthe intermediate starts to crystallize. Filtration and drying yielded4.47 g of the intermediate as yellow crystalline solid.

B) 3-Benzothiazol-2-yl-3,5-dichloro-1,3-dihydroindol-2-one

Pyridine (0.57 ml) and thionyl chloride (0.42 ml) were successivelyadded to an ice-cooled solution of the intermediate from Step A (1.27 g,4.0 mmol) in dichloromethane (40 ml). The reaction mixture was stirredat 0° C. for 1 h and then saturated ammonium chloride solution wasadded. The organic phase was dried over magnesium sulfate, filtered andconcentrated under reduced pressure. The crude intermediate was rapidlyemployed without further purification in the next step.

C)(2S,4R)-1-(3-Benzothiazol-2-yl-5-chloro-2-oxo-2,3-dihydro-1H-indol-3-yl)-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide

(2S,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid dimethylamidehydrochloride (0.78 g, 4.0 mmol) was added to a solution of theintermediate from Step B in a mixture of dichloromethane (9 ml), THF (2ml) and DIPEA (2 ml). The reaction mixture was stirred at roomtemperature for 48 h. After addition of water, the mixture was extractedfour times with ethyl acetate. The combined organic layer was dried overmagnesium sulfate, filtered and concentrated under reduced pressure. Theless polar diastereomer, as judged by thin-layer-chromatography using 5%MeOH in dichloromethane, precipitated on concentration and was filteredoff. Purification by chromatography (silica gel, 5% MeOH indichloromethane) resulted in 0.28 g of the less polar diastereomer.Purification by chromatography (silica gel, 5% MeOH in dichloromethane)of the mother liquor resulted in 0.36 g of the more polar diastereomer.

Example 1(2S,4R)-1-[3-Benzothiazol-2-yl-5-chloro-1-(2,4-dimethoxy-benzenesulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, dextrorotatory diastereomer

Sodium hydride (12 mg of 60% dispersion in mineral oil, 0.3 mmol) wasadded to an ice-cold solution of the less polar diastereomerintermediate from Step C (115 mg, 0.25 mmol) in DMF (1.5 ml). Thereaction mixture was stirred at 0° C. for 1 h and then2,4-dimethoxy-benzene-sulfonyl chloride (71 mg, 0.3 mmol) was added.After the reaction mixture had been stirred at room temperature for onehour, water was added and the mixture was extracted with ethyl acetate.The organic layer was washed with water and saturated brine and driedover magnesium sulfate. Purification by chromatography (silica gel, 5%MeOH in dichloromethane) resulted in 93 mg of Example 1 as a whitesolid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.15 (1H), 7.95 (1H), 7.75 (2H), 7.50 (3H),7.20 (1H), 6.80 (1H), 6.75 (1H), 4.80 (1H), 4.25 (1H), 3.90 (3H), 3.85(1H), 3.50 (3H), 3.25 (1H), 2.60 (3H), 1.85 (1H), 1.75 (1H); MS (API-ES,pos) m/z=657 [M+H]

Example 2(2S,4R)-1-[3-Benzothiazol-2-yl-5-chloro-1-(2,4-dimethoxy-benzenesulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

The diastereomer product was prepared by the method described in theprevious paragraph starting from the more polar diastereomerintermediate from Step C. Purification by chromatography (silica gel, 5%MeOH in dichloromethane) resulted in Example 2 as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (1H), 7.95 (1H), 7.75 (1H), 7.65 (1H),7.45 (4H), 6.80 (1H), 6.75 (1H), 4.85 (1H), 4.70 (1H), 4.30 (1H), 3.90(3H), 3.60 (1H), 3.40 (3H), 2.83 (1H), 2.55 (3H), 2.45 (3H), 2.10 (1H),1.80 (1H); MS (API-ES, pos) m/z=657 [M+H]

Example 3 and Example 4(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2,4-dimethoxy-pyrimidin-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide A)5-Chloro-3-(2,4-dimethoxy-pyrimidin-5-yl)-3-hydroxy-1,3-dihydroindol-2-one

A 1.6 M solution of n-butyllithium in hexane (10 ml, 16 mmol) was addeddropwise to a solution of 5-bromo-2,4-dimethoxypyrimidine (3.29 g, 15mmol) in THF (50 ml) at −78° C. After stirring at −78° C. for 0.5 h, asuspension of 5-chloroisatin (1.27 g, 7.0 mmol) in THF (50 ml) was addeddropwise. The reaction mixture was allowed to warm to room temperatureand then saturated ammonium chloride solution was added. The mixture wasextracted three times with ethyl acetate, and the combined organiclayers were washed with saturated brine. The organic phase was driedover magnesium sulfate, filtered and concentrated under reducedpressure. Purification by chromatography (silica gel, 50% ethyl acetatein dichloromethane) resulted in 0.97 g of the intermediate.

B) 3,5-Dichloro-3-(2,4-dimethoxy-pyrimidin-5-yl)-1,3-dihydroindol-2-one

Pyridine (0.28 ml) and thionyl chloride (0.18 ml) were addedsuccessively to an ice-cold solution of the intermediate from Step A(0.64 g, 2.0 mmol) in dichloromethane (20 ml). The reaction mixture wasstirred at 0° C. for 1 h and then saturated ammonium chloride solutionwas added. The organic phase was dried over magnesium sulfate, filteredand concentrated under reduced pressure. The crude intermediate wasrapidly employed without further purification in the next step.

C)(2S,4R)-1-[5-Chloro-3-(2,4-dimethoxy-pyrimidin-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide

(2S,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid dimethylamidehydrochloride (0.39 g, 2.0 mmol) was added to a solution of theintermediate from Step B in a mixture of dichloromethane (4 ml), THF (1ml) and DIPEA (1 ml). The reaction mixture was stirred at roomtemperature for 18 h. After addition of water, the mixture was extractedfour times with ethyl acetate. The combined organic phase was dried overmagnesium sulfate, filtered and concentrated under reduced pressure.Purification by chromatography (silica gel, 7% MeOH in dichloromethane)resulted in 0.45 g of the mixture of diastereomers (ratio about 2:1).

D)(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2,4-dimethoxy-pyrimidin-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide

Sodium hydride (12 mg of 60% dispersion in mineral oil, 0.3 mmol) wasadded to an ice-cold solution of the mixture of diastereomers from StepC (139 mg, 0.30 mmol) in DMF (1.5 ml). The reaction mixture was stirredat 0° C. for 0.5 h and then 2,4-dimethoxy-benzenesulfonyl chloride (71mg, 0.3 mmol) was added. After the reaction mixture had been stirred atroom temperature for one hour, water was added, and the mixture wasextracted with ethyl acetate.

The organic layer was washed with water and saturated brine and driedover magnesium sulfate. Purification by chromatography (silica gel, 5%MeOH in dichloromethane) resulted in 63 mg of the less polardiastereomer (levorotatory isomer) and 25 mg of the more polardiastereomer (dextrorotatory isomer) as colorless waxes.

Example 3(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2,4-dimethoxy-pyrimidin-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

This diastereomer is the less polar diastereomer from Step D.

¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (1H), 7.97 (1H), 7.75 (1H), 7.45 (1H),7.20 (1H), 6.75 (2H), 4.95 (1H), 4.55 (1H), 4.30 (1H), 3.90 (6H), 3.75(3H), 3.37 (3H), 3.05 (1H), 1.75 (1H), 1.65 (1H); MS (API-ES, pos)m/z=662 [M+H]

Example 4(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2,4-dimethoxy-pyrimidin-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, dextrorotatory diastereomer

This diastereomer is the more polar diastereomer from Step D.

¹H NMR (400 MHz, DMSO-d₆) δ 8.95 (1H), 7.95 (1H), 7.80 (1H), 7.50 (1H),6.80 (2H), 6.70 (1H), 4.70 (1H), 4.20 (1H), 3.90 (6H), 3.75 (3H), 3.65(1H), 3.40 (3H), 3.00 (1H), 2.80 (1H), 2.65 (3H), 2.45 (3H), 1.70 (2H);MS (API-ES, pos) m/z=662 [M+H]

Example 5 and Example 6(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide A)5-Chloro-3-(2-methoxy-pyridin-3-yl)-3-hydroxy-1,3-dihydroindol-2-one

A 1.7 M solution of tert-butyllithium in pentane (28.9 ml, 49.1 mmol)was added to THF (100 ml) at −78° C. 2-Bromomesitylene (3.6 ml, 23.4mmol) was added dropwise and the mixture stirred at −78° C. for 1 h.2-Methoxypyridine (1.92 ml, 18 mmol) was added at −78° C. and then themixture was stirred at 0° C. for 1 h and at ambient temperature for 0.5h. A suspension of 5-chloroisatin (1.27 g, 9.0 mmol) in THF (50 ml) wasadded dropwise at −78° C. The reaction mixture was allowed to warm toroom temperature and then saturated ammonium chloride solution wasadded. The mixture was extracted three times with ethyl acetate, and thecollected extracts were washed with saturated brine. The organic phasewas dried over magnesium sulfate, filtered and concentrated underreduced pressure. Purification by crystallization from dichloromethaneyielded 1.1 g of the intermediate.

B) 3,5-Dichloro-3-(2-methoxy-pyridin-3-yl)-1,3-dihydroindol-2-one

Pyridine (0.33 ml) and thionyl chloride (0.30 ml) were addedsuccessively to an ice-cold solution of the intermediate from Step A(1.1 g, 3.44 mmol) in dichloromethane (10 ml). The reaction mixture wasstirred at 0° C. for 1 h and then saturated ammonium chloride solutionwas added. The organic phase was dried over magnesium sulfate, filteredand concentrated under reduced pressure. The crude intermediate wasrapidly employed without further purification in the next step.

C)(2S,4R)-1-[5-Chloro-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide

(2S,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid dimethylamidehydrochloride (0.67 g, 3.44 mmol) was added to a solution of theintermediate from Step B in a mixture of dichloromethane (10 ml), THF (2ml) and DIPEA (1.6 ml). The reaction mixture was stirred at roomtemperature for 18 h. After addition of water, the mixture was extractedfour times with ethyl acetate. The combined organic phase was dried overmagnesium sulfate, filtered and concentrated under reduced pressure.Purification by chromatography (silica gel, 5% MeOH in dichloromethane)resulted in 0.58 g of the more polar diastereomer, 0.2 g of the lesspolar diastereomer and 0.4 g of a mixture of diastereomers (ratio about1:1).

Example 5(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

Sodium hydride (14.4 mg of 60% dispersion in mineral oil, 0.36 mmol) wasadded to an ice-cold solution of the more polar diastereomerintermediate from Step C (150 mg, 0.35 mmol) in DMF (3.2 ml). Thereaction mixture was stirred at 0° C. for 1 h and then2,4-dimethoxy-benzenesulfonyl chloride (86.2 mg, 0.364 mmol) was added.After the reaction mixture had been stirred at room temperature for onehour, water was added, and the mixture was extracted with ethyl acetate.The organic layer was washed with water and brine and dried overmagnesium sulfate. Purification by chromatography (silica gel, 5% MeOHin dichloromethane) and trituration with diethyl ether (6 ml) and hexane(6 ml) resulted in 130 mg of the levorotatory diastereomer as a whitesolid.

[α]_(D) ^(20° C). (c=0.1, CHCI₃): −233;

¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (1H), 8.10 (1H), 8.00 (1H), 7.80 (1H),7.45 (1H), 7.00 (2H), 6.75 (2H), 4.95 (1H), 4.55 (1H), 4.35 (1H), 3.85(3H), 3.75 (3H), 3.35 (3H), 3.00 (1H), 2.55 (3H), 2.45 (3H), 1.65 (2H);MS (API-ES, pos) m/z=631 [M+H]

Example 6(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, dextrorotatory diastereomer

The diastereomer product was prepared by the method described in theprevious paragraph starting from the less polar diastereomerintermediate from Step C. Purification by chromatography (silica gel, 5%MeOH in dichloromethane) and trituration with diethyl ether/hexaneresulted in the dextrorotatory diastereomer as a white solid.

[α]_(D) ^(20° C). (c=0.1, CHCI₃): +142;

¹H NMR (400 MHz, DMSO-d₆) δ 8.45 (1H), 8.13 (1H), 7.97 (1H), 7.80 (1H),7.50 (1H), 7.20 (1H), 6.80 (2H), 6.55 (1H), 4.70 (1H), 4.25 (1H), 3.90(3H), 3.80 (3H), 3.65 (1H), 3.35 (3H), 3.00 (1H), 2.75 (1H), 2.65 (3H),2.40 (3H), 1.70 (2H); MS (API-ES, pos) m/z=631 [M+H]

The following compounds can be prepared in an analogous fashion toExamples 1 to 6 employing the synthetic route that is outlined insynthesis Scheme 1:

Example 7(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methyl-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide Example 8(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-chloropyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide Example 9(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(3-methoxy-pyridin-2-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidin-2-carboxylicacid dimethylamide, levorotatory diastereomer A)5-Chloro-3-hydroxy-3-(3-methoxy-pyridin-2-yl)-1,3-dihydro-indol-2-one

A 1.7 M solution of tert-butyllithium in pentane (57.8 mL) was added toTHF (200 ml) at −78° C. 2-Bromomesitylene (3.6 mL) was added dropwise,keeping the temperature below −60° C., and the mixture stirred at −78°C. for 1 h. 3-Methoxypyridine (3.6 mL) was added dropwise at −78° C. andthen the mixture was stirred between −30° C. and −20° C. The reactionmixture was re-cooled to −78° C. and a slurry of 5-chloroisatin (3.26 g)in THF (100 mL) was added portionwise, keeping the temperature below−60° C. The reaction mixture was stirred at −78° C. for 1 h. The coolingbath was removed and the reaction mixture was stirred for 30 min. Thereaction mixture was quenched with 10% aqueous ammonium chloridesolution and extracted several times with ethyl acetate. The combinedorganic layers were washed with water, dried over magnesium sulfate andevaporated to low volume. Upon standing, 1.05 g of a cream-colored solidseparated which was filtered off, washed with ethyl acetate and dried invacuo.

The subsequent steps were performed in analogous fashion to Examples 5and 6.

Example 9

¹H NMR (400 MHz, DMSO-d₆) δ 8.15 (1H), 7.95 (1H), 7.75 (1H), 7.43 (3H),6.90 (1H), 6.75 (2H), 5.75 (1H), 4.70 (1H), 4.20 (1H), 3.90 (3H), 3.75(3H), 3.25 (3H), 3.05 (1H), 2.70 (3H), 2.45 (3H), 1.95 (1H), 1.60 (1H);MS (API-ES, pos) m/z 631 [M+H]

Example 10(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(4-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer A)5-Chloro-3-hydroxy-3-(4-methoxy-pyridin-3-yl)-1,3-dihydro-indol-2-one

A 1.7 M solution of tert-butyllithium in pentane (43.4 mL) was added toTHF (150 ml) at −78° C. 2-Bromomesitylene (5.4 mL) was added dropwise,keeping the temperature below −60° C., and the mixture stirred at −78°C. for 1 h. 4-Methoxypyridine (2.75 mL) was added dropwise at −78° C.and then the mixture was stirred at −30° C. to −20° C. for 3.5 h. Thereaction mixture was re-cooled to −78° C. and a slurry of 5-chloroisatin(2.44 g) in THF (120 ml) was added portionwise, keeping the temperaturebelow −65° C. The reaction mixture was stirred at −78° C. for 30 min.The reaction mixture was allowed to warm to −20° C. and then 10% aqueousammonium chloride solution (75 mL) was added. After stirring for 10 min,the white solid was filtered off, washed with water (excess) and ethylacetate (20 mL). Yield after drying in vacuo: 1.8 g (42%).

MS (API-ES, pos) m/z=383 [M+H]

The subsequent steps were performed in analogous fashion to Examples 5and 6.

Example 10

¹H NMR (400 MHz, DMSO-d₆) δ 8.85 (1H), 8.40 (1H), 8.00 (1H), 7.75 (1H),7.45 (1H), 7.05 (1H), 6.95 (1H), 6.75 (2H), 4.95 (1H), 4.60 (1H), 4.35(1H), 3.85 (3H), 3.75 (3H), 3.35 (3H), 3.00 (1H), 2.55 (3H), 2.45 (3H),1.60 (2H); MS (API-ES, pos) m/z=631 [M+H]

Example 11(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(4-methyl-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide Example 12(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-pyrazin-2-yl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide Example 13(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(3-methoxy-pyrazin-2-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer A)5-Chloro-3-hydroxy-3-(3-methoxy-pyrazin-2-yl)-1,3-dihydro-indol-2-one

n-BuLi (26 mmol, 16.3 mL of a 1.6M solution in hexanes) was addeddropwise to a solution of 2,2,6,6-tetramethylpiperidine (26 mmol, 4.4mL) in THF (150 mL) at 0° C. After stirring for 30 min at 0° C., thesolution was cooled to −78° C. and a solution of 2-methoxypyrazine (20mmol, 1.93 mL) in THF (30 mL) was added dropwise. After stirring at −78°C. for 15 min, a suspension of 5-chloroisatin (10 mmol, 1.82 g) in THF(50 mL) was added. The reaction mixture was stirred at 0° C. for 2 h,then saturated ammonium chloride solution was added. The mixture wasextracted three times with ethyl acetate, and the collected extractswere washed with saturated brine. The organic phase was dried overmagnesium sulfate, filtered and concentrated under reduced pressure.Purification by crystallization from diethyl ether yielded 1.14 g of therequired intermediate.

The subsequent steps were performed in analogous fashion to Examples 5and 6.

Example 13

¹H NMR (500 MHz, DMSO-d₆) δ 8.23 (1H), 8.17 (1H), 7.95 (1H), 7.75 (1H),7.47 (1H), 7.15 (1H), 6.75 (2H), 5.05 (1H), 4.65 (1H), 4.25 (1H), 3.87(3H), 3.67 (3H), 3.50 (3H), 3.00 (1H), 2.65 (3H), 1.90 (1H), 1.65 (1H);MS (API-ES, pos) m/z=632 [M+H]

Example 14(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(3,6-dimethoxy-pyridazin-4-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide Example 15(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(isoquinolin-4-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide Example 16(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(quinolin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide Example 17(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(thiazol-2-yl)-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide Example 18(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(1-methyl-1H-benzimidazol-2-yl)-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide Example 19(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(1-methyl-1H-imidazol-2-yl)-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide Example 20(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(benzoxazol-2-yl)-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide Example 21(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(3-methyl-benzo[b]thiophen-2-yl)-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide Example 22(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(3-methyl-thiophen-2-yl)-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide Example 23(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(benzo[b]thiophen-7-yl)-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide Example 24(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(benzofuran-7-yl)-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethyl amide Example 25(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(benzofuran-2-yl)-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide Example 26(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(3-methyl-furan-2-yl)-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide Example 27(2S,4R)-1-[5-Chloro-1-2,4-dimethoxy-benzenesulfonyl)-3-furan-3-yl-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide Example 28(2S,4R)-1-[5-Chloro-3-(2-methoxy-phenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer A)5-Chloro-3-hydroxy-3-(2-methoxy-phenyl)-1,3-dihydroindol-2-one

Magnesium turnings (40 g, 1.65 mol) are introduced into diethyl ether(100 ml) and, while stirring, a solution of 2-bromoanisole (206 ml, 1.65mol), in diethyl ether (450 ml) is added dropwise. The reaction can beinitiated, if necessary, by adding iodine crystals. During the addition,the reaction mixture should boil gently. After the addition, the mixturewas stirred at room temperature for 1 hour. A slurry of 5-chloroisatin(75 g, 0.41 mol) in THF (750 ml) was added to the Grignard solutionwhile cooling slightly (temperature 18-24° C.), and the mixture wasstirred at room temperature for 30 min. The reaction mixture was stirredinto ammonium chloride solution and extracted several times with ethylacetate. The combined organic phase was washed four times with water,dried over magnesium sulfate and concentrated under reduced pressure.The remaining residue was stirred with 2-propanol. The resultingprecipitate was filtered off, washed with 2-propanol and diethyl etherand dried. 106 g of the desired intermediate were obtained.

B)(2S,4R)-1-[5-Chloro-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide

Pyridine (56 ml) and thionyl chloride (38 ml) were successively addeddropwise to an ice-cold solution of the intermediate from Step A (100 g,0.345 mol) in dichloromethane (1 000 ml). The reaction mixture wasstirred at 0° C. for 30 min and then stirred into ice-water. The organicphase was separated, and the aqueous phase was extracted once more withdichloromethane. The combined organic phase was washed several timeswith water, dried over magnesium sulfate and concentrated under reducedpressure. The residue was stirred with hot toluene. The resultingcrystals were filtered off in the cold, washed with toluene and pentaneand dried. 79 g of the desired 3-chloro intermediate were obtained.

(2S,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid dimethylamidehydrochloride (12.6 g, 65 mmol) was added to a solution of the 3-chlorointermediate (20.0 g, 65 mmol) in dichloromethane (400 ml) and DIPEA (28ml, 162 mmol). The solution was stirred at room temperature overnight.The reaction mixture was diluted with dichloromethane and washed withdilute sodium bicarbonate and several times with water. The organicphase was dried over magnesium sulfate and concentrated under reducedpressure. The residue was recrystallized from acetone. 6.5 g of the lesspolar (as judged by thin-layer-chromatography on silica gel, 7% MeOH indichloromethane) diastereomer were obtained. The mother liquor wasconcentrated under reduced pressure. Purification of the remainingresidue by chromatography (silica gel, 7% MeOH in dichloromethane)resulted in 1.0 g of the less polar diastereomer and 17.3 g of the morepolar diastereomer.

C)(2S,4R)-1-[5-Chloro-3-(2-methoxy-phenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

Potassium tert-butoxide (38 mg, 0.34 mmol) was added to an ice-coldsolution of the more polar diastereomer from Step B (150 mg, 0.34 mmol)in DMF (3 ml), and the mixture was stirred at 0° C. for 30 min. Afteraddition of 8-quinolinesulfonyl chloride (79 mg, 0.34 mmol), thereaction mixture was left to stir at room temperature for 3 hours. Waterwas added to the reaction mixture, which was then extracted with ethylacetate. The organic layer was washed with water and saturated brine anddried over magnesium sulfate. Purification by chromatography (silicagel, 7% MeOH in dichloromethane) resulted in 159 mg of the product.

[α]_(D) ^(20° C). (c=0.20, CHCI₃): −148;

¹H-NMR (D₆-DMSO): δ=1.4-1.6 (5H), 1.7 (2H), 1.9 (2H), 2.15-2.35 (4H),2.45 (3H), 2.9 (2H), 3.25 (4H), 3.7 (3H), 4.15 (2H), 6.55 (1H), 6.6(1H), 6.75-6.90 (3H), 7.05-7.2 (2H), 7.40 (1H), 7.65 (1H), 7.9 (1H), 8.0(1H), 8.15 (1H) and 8.85 (1H) ppm; MS (API-ES, pos) m/z=621 [M+H]

Examples 29 to 61 can be prepared in analogous fashion to Example 28using Example 28B (more polar diastereomer) as the starting material inthe sulfonylation reaction. Heterocyclic sulfonyl chlorides wereacquired from commercial suppliers or synthesized according to standardmethods, for example according to the following procedure:

5-Methyl-pyridine-2-sulfonyl chloride

Chlorine gas was bubbled through a solution of2-mercapto-5-methylpyridine (64 mmol, 8.00 g, from Ubichem) in conc.hydrochloric acid (80 mL) at 0° C. After 1 h, the reaction mixture waspoured into an ice-water mixture (200 mL). The suspension was extractedseveral times with dichloromethane and the combined organic layers werewashed with sodium, bicarbonate solution. After drying over sodiumsulfate, the volatiles were evaporated in vacuo to yield 9.80 g (80%) ofatolorless oil which solidified in the refrigerator.

5-Trifluoromethyl-pyridine-2-sulfonyl chloride,5-Bromo-pyridine-2-sulfonyl chloride,5-Bromo-3-methyl-pyridine-2-sulfonyl chloride, Pyridine-2-sulfonylchloride, 4-Methyl-pyridine-2-sulfonyl chloride,6-Methyl-pyridine-2-sulfonyl chloride, 5-Chloro-pyridine-2-sulfonylchloride were prepared in analogous fashion.

Example 29(2S,4R)-1-[5-Chloro-3-(2-methoxy-phenyl)-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H-NMR (D₆-DMSO): δ=1.65 (1H), 2.05 (1H), 2.4-2.6 (6H), 2.8 (1H), 3.0(3H), 3.1 (1H), 4.3 (1H), 4.45 (1H), 4.95 (1H, OH), 6.8 (1H), 6.9 (1H),7.0 (1H), 7.25-7.35 (2H), 7.4 (1H), 7.65 (1H) and 8.0-8.2 (3H) ppm; MS(API-ES, pos) m/z=576 [M+H]

Example 30(2S,4R)-1-[5-Chloro-3-(2-methoxy-phenyl)-2-oxo-1-(thiophene-3-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide trifluoroacetate Example 31(2S,4R)-1-[5-Chloro-1-(5-chloro-thiophene-2-sulfonyl)-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicaciddimethylamide, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.12, CHCI₃): −131;

¹H-NMR (D₆-DMSO): δ=1.7 (1H), 2.0 (1H), 2.35-2.55 (6H), 2.65 (1H), 2.95(1H), 3.2 (3H), 4.25 (1H), 4.45 (1H), 4.7 (broad, 1H, OH), 6.8 (1H), 6.9(1H), 7.0 (1H), 7.25 (1H), 7.30 (1H), 7.35 (1H), 7.60 (1H), 7.90 (1H)and 8.05 (1H) ppm.

Example 32(2S,4R)-1-[1-(3-Bromo-5-chloro-thiophene-2-sulfonyl)-5-chloro-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.17, CHCI₃): −142;

¹H-NMR (CDCI₃) δ=1.75 (1H), 1.9 (1H), 2.3 (1H), 2.4 (3H), 2.75 (3H), 3.3(1H), 3.6 (3H), 4.65 (1H), 4.8 (1H), 6.8 (1H), 7.0 (2H), 7.1 (1H), 7.3(1H), 7.8 (1H) and 7.9 (1H) ppm.

Example 33(2S,4R)-1-[1-(4-Bromo-5-chloro-thiophene-2-sulfonyl)-5-chloro-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide trifluoroacetate Example 34(2S,4R)-1-[5-Chloro-1-(5-methyl-thiophene-2-sulfonyl)-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide Example 35(2S,4R)-1-[5-Chloro-1-(4,5-dichloro-thiophene-2-sulfonyl)-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide trifluorocetate Example 36(2S,4R)-1-[5-Chloro-1-(3-methylbenzo[b]thiophene-2-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide Example 37(2S,4R)-1-[1-(Benzo[b]thiophene-2-sulfonyl)-5-chloro-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicaciddimethylamide, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.18, CHCI₃): −146;

¹H-NMR (D₆-DMSO): S=1.65 (1H), 2.0 (1H), 2.3-2.5 (7H), 2.75 (1H), 2.85(3H), 4.3 (1H), 4.45 (1H), 4.9 (1H, OH), 6.8 (1H), 6.95 (1H), 7.0 (1H),7.25 (1H), 7.45 (1H), 7.55 (1H), 7.6 (1H), 7.7 (1H), 8.05 (1H), 8.1(1H), 8.15 (1H), and 8.55 (1H) ppm.

Example 38(2S,4R)-1-[5-Chloro-1-(5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.19, CHCI₃): −104;

¹H-NMR (CDCI₃): δ=1.7 (2H), 2.4 (3H), 2.5-2.8 (4H), 2.9 (3H), 3.3-3.5(4H), 4.55 (1H), 4.7 (1H), 6.7 (1H), 7.0 (1H), 7.1 (1H), 7.25 (1H), 7.45(1H), 7.75 (1H) and 7.7-7.9 (3H) ppm.

Example 39(2S,4R)-1-[5-Chloro-3-(2-methoxy-phenyl)-1-(1-methyl-1H-imidazole-4-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.20, CHCI₃): −152;

¹H-NMR (D₆-DMSO): δ=1.7 (2H), 2.3-2.5 (8H), 3.1 (3H), 3.75 (3H), 4.35(1H), 4.55 (1H), 4.9 (1H, OH), 6.85 (1H), 6.9 (1H), 7.0 (1H), 7.3 (1H),7.4 (1H), 7.75 (1H), 7.85 (1H) and 8.25 (1H) ppm.

Example 40(2S,4R)-1-[5-Chloro-1-(1,2-dimethyl-1H-imidazole-4-sulfonyl)-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.20, CHCI₃): −161

Example 41(2S,4R)-1-[5-Chloro-1-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl)-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide trifluoroacetate Example 42(2S,4R)-1-[5-Chloro-3-(2-methoxy-phenyl)-2-oxo-1-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide trifluoroacetate Example 43(2S,4R)-1-[5-Chloro-3-(2-methoxy-phenyl)-1-(5-methyl-1-phenyl-1H-pyrazole-4-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide trifluoroacetate Example 44(2S,4R)-1-[5-Chloro-1-(3,5-dimethyl-isoxazole-4-sulfonyl)-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicaciddimethylamide trifluoroacetate Example 45(2S,4R)-1-[5-Chloro-1-(2,4-dimethyl-thiazole-5-sulfonyl)-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicaciddimethylamide, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.21, CHCI₃): −152;

¹H-NMR (CDCI₃) δ=1.75 (1H), 1.9 (1H), 2.4 (3H), 2.6-2.9 (10H), 3.3 (1H),3.5 (3H), 4.6 (1H), 4.75 (1H), 6.75 (1H), 6.95 (1H), 7.1 (1H), 7.2 (2H),7.8 (1H) and 7.9 (1H) ppm; MS (API-ES, pos) m/z=605 [M+H]

Example 46(2S,4R)-1-[5-Chloro-1-(6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl)-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.22, CHCI₃): −127;

MS (API-ES, pos) m/z=650 [M+H]

Example 47(2S,4R)-1-[5-Chloro-3-(2-methoxy-phenyl)-2-oxo-1-(pyridine-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (1H), 8.35 (1H), 8.25 (1H), 8.00 (1H),7.80 (2H), 7.45 (1H), 7.30 (1H), 7.00 (1H), 6.95 (1H), 6.85 (1H), 4.95(1H), 4.50 (1H), 4.30 (1H), 3.10 (3H), 2.45 (4H), 1.65 (1H); MS (API-ES,pos) m/z=571 [M+H]

Example 48(2S,4R)-1-[1-(5-Bromo-pyridine-2-sulfonyl)-5-chloro-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H NMR (400 MHz, DMSO-d₆) δ 8.95 (1H), 8.50 (1H), 8.30 (1H), 8.00 (1H),7.77 (1H), 7.40 (1H), 7.30 (1H), 7.03 (1H), 6.97 (1H), 6.90 (1H), 4.90(1H), 4.45 (1H), 4.30 (1H), 3.27, 2.40 (4H), 1.60 (1H); MS (API-ES, pos)m/z=649 [M+H]

Example 49(2S,4R)-1-[5-Chloro-1-(5-trifluoro-methyl-pyridine-2-sulfonyl)-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide Example 50(2S,4R)-1-[5-Chloro-1-(5-methoxy-pyridine-2-sulfonyl)-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide Example 51(2S,4R)-1-[5-Chloro-3-(2-methoxy-phenyl)-1-(5-methyl-pyridine-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H NMR (400 MHz, DMSO-d₆) δ 8.63 (1H), 8.25 (1H), 8.00 (2H), 7.80 (1H),7.40 (1H), 7.25 (1H), 7.00 (1H), 7.95 (1H), 6.85 (1H), 4.90 (1H), 4.50(1H), 4.30 (1H), 3.15, 2.45 (7H), 1.65 (1H); MS (API-ES, pos) m/z=585[M+H]

Example 52(2S,4R)-1-[5-Chloro-1-(5-chloro-pyridine-2-sulfonyl)-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H NMR (400 MHz, DMSO-d₆) δ 8.85 (1H), 8.35 (2H), 8.00 (1H), 7.75 (1H),7.40 (1H), 7.30 (1H), 7.00 (2H), 6.40 (1H), 4.90 (1H), 4.40 (1H), 4.30(1H), 3.30, 2.40, 1.60 (1H); MS (API-ES, pos) m/z=605 [M+H]

Example 53(2S,4R)-1-[1-(5-Bromo-3-methyl-pyridine-2-sulfonyl)-5-chloro-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H NMR (400 MHz, DMSO-d₆) δ 8.75 (1H), 8.40 (1H), 8.00 (1H), 7.70 (1H),7.40 (1H), 7.30 (1H), 7.00 (2H), 6.93 (1H), 5.00 (1H), 4.50 (1H), 4.35(1H), 3.45 (3H), 2.80 (3H), 2.35, 1.65 (1H); MS (API-ES, pos) m/z=663[M+H]

Example 54(2S,4R)-1-[5-Chloro-1-(3,5-dimethyl-pyridine-2-sulfonyl)-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H NMR (400 MHz, DMSO-d₆) δ 8.43 (1H), 7.95 (1H), 7.85 (1H), 7.75 (1H),7.40 (1H), 7.30 (1H), 7.00 (2H), 6.90 (1H), 4.95 (1H), 4.55 (1H), 4.40(1H), 3.40 (3H), 2.75 (3H), 2.35, 1.63 (1H); MS (API-ES, pos) m/z=599[M+H]

Example 55(2S,4R)-1-[5-Chloro-3-(2-methoxy-phenyl)-2-oxo-1-(pyridine-3-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H NMR (400 MHz, DMSO-d₆) δ 9.33 (1H), 8.90 (1H), 8.60 (1H), 8.10 (1H),7.75 (2H), 7.40 (1H), 7.30 (1H), 7:05 (1H), 7.00 (1H), 6.85 (1H), 4.95(1H), 4.45 (1H), 4.20 (1H), 3.20 (3H), 3.15 (1H), 2.70 (1H), 2.30 (3H),2.00 (1H), 1.60 (1H); MS (API-ES, pos) m/z=571 [M+H]

Example 56(2S,4R)-1-[5-Chloro-3-(2-methoxy-phenyl)-1-(6-morpholin-4-yl-pyridine-3-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H NMR (400 MHz, DMSO-d₆) δ 8.75 (1H), 8.12 (1H), 8.00 (1H), 7.70 (1H),7.37 (1H), 7.30 (1H), 7.00 (2H), 6.93 (1H), 6.87 (1H), 4.90 (1H), 4.47(1H), 4.25 (1H), 3.65 (8H), 3.20 (3H), 2.30-2.45 (5H), 2.00 (1H), 1.65(1H); MS (API-ES, pos) m/z=656 [M+H]

Example 57(2S,4R)-1-[5-Chloro-3-(2-methoxy-phenyl)-2-oxo-1-(6-phenoxy-pyridine-3-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide trifluoroacetate Example 58(2S,4R)-1-[5-Chloro-1-(6-methoxypyridine-3-sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide Example 59(2S,4R)-1-[5-Chloro-1-(5-bromo-6-chloropyridine-3-sulfonyl)-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide Example 60(2S,4R)-1-[5-Chloro-3-(2-methoxy-phenyl)-1-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide trifluoroacetate Example 61(2S,4R)-1-[5-Chloro-3-(2-methoxy-phenyl)-2-oxo-1-(1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

(−)-(2S,4R)-1-{5-Chloro-3-(2-methoxy-phenyl)-2-oxo-1-[2-(2,2,2-trifluoro-acetyl)-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl]-2,3-dihydro-1H-indol-3-yl}-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide (obtained from Example 28B (more polar diastereomer)and commercially available2-(2,2,2-Trifluoro-acetyl)-1,2,3,4-tetrahydro-isoquinoline-7-sulfonylchloride) (1.39 mmol, 1.00 g) was deprotected using K₂CO₃ (1 eq.) at RTfor 6 h in a 9:1 MeOH:H₂O mixture (22 mL). The solution was evaporatedin vacuo. The residue was dissolved in a 1:1 CH₂Cl₂:H₂O mixture and thephases were separated. The organic phase was dried over magnesiumsulfate and evaporated in vacuo to afford 850 mg of the requiredproduct.

¹H-NMR (400 MHz, DMSO-d₆) δ 9.06 (2H, s br.), 8.22-7.91 (3H, m), 7.72(1H, d), 7.56 (1H, d), 7.38 (1H, d), 7.27 (1H, t), 7.02 (1H, t), 6.96(1H, s), 6.83 (1H, d), 3.40 (2H, s br.), 3.08 (2H, t), 3.02 (2H, s br.),2.05 (1H, m br.), 1.72-1.57 (1H, m); MS (API-ES, pos) m/z=625 [M+H]

Example 625-Chloro-1-(2,4-dimethox-benzenesulfonyl)-3-hydroxy-3-(3-methyl-thiophen-2-yl)-1,3-dihydro-indol-2-oneA) 5-Chloro-3-hydroxy-3-(3-methyl-thiophen-2-yl)-1,3-dihydro-indol-2-one

Magnesium turnings (6.8 g, 0.27 mmol) are introduced into diethyl ether(30 ml), and, while stirring, a solution of 2-bromo-3-methyl-thiophene(50 g, 0.282 mol) in diethyl ether (100 ml) is added dropwise. Thereaction can be initiated if necessary by adding iodine crystals. Duringthe addition, the reaction mixture should boil gently. After theaddition, the mixture was stirred at room temperature for 1 hour. Asuspension of 5-chloroisatin (19 g, 0.105 mol) in THF (200 ml) was addedto the Grignard solution while cooling slightly (temperature 18-24° C.)and the mixture was stirred at room temperature for 30 min. The reactionmixture was stirred into ammonium chloride solution and extractedseveral times with ethyl acetate. The combined organic phases werewashed with saturated brine, dried over magnesium sulfate andconcentrated under reduced pressure. The residue was stirred withdiethyl ether. The resulting precipitate was filtered off, washed withdiethyl ether and dried. 26 g of the desired intermediate were obtained.

B)5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-hydroxy-3-(3-methyl-thiophen-2-yl)-1,3-dihydro-indol-2-one

Potassium tert-butoxide (1.21 g, 10.8 mmol) was added to an ice-coldsolution of the intermediate from Step A (3.00 g, 10.8 mmol) in DMF (30ml), and the mixture was stirred at 0° C. for 30 min. After addition of2,4-dimethoxy-benzenesulfonyl chloride (2.5 g, 10.8 mmol), the reactionmixture was left to stir at 0° C. for 1 hour. Further addition of 0.2equivalent each of potassium tert-butoxide and sulfonyl chloride led tono further advance in the reaction according to thin-layerchromatography. The reaction mixture was stirred into dilute potassiumcarbonate solution, and the resulting precipitate was filtered off. Theprecipitate was taken up in ethyl acetate, and the extract was washedwith saturated brine and dried over magnesium sulfate. Purification bychromatography (silica gel, gradient 30% to 50% ethyl acetate inheptane) and recrystallization from diethyl ether resulted in 0.96 g ofthe desired product.

¹H-NMR (D₆-DMSO) δ=1.55 (3H), 3.6 (3H), 3.85 (3H), 6.7 (1H), 6.75 (2H),7.2 (1H), 7.35 (1H), 7.55 (1H), 7.6 (1H), 7.8 (1H) and 7.9 (1H) ppm.

Example 63 (4-Chloro-phenyl)-carbamic acid5-chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(3-methyl-thiophen-2-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester

4-Chlorophenyl isocyanate (32 mg, 0.208 mmol) and DMAP (5 mg) weresuccessively added to a solution of Example 62 (100 mg, 0.21 mmol) intoluene (20 ml) and stirred at 90° C. for 30 min. The solvent wasremoved under reduced pressure, and the residue was taken up in ethylacetate. The organic phase was washed with dilute citric acid solutionand saturated sodium chloride solution, dried over magnesium sulfate andconcentrated under reduced pressure. Recrystallization from methanolresulted in 80 mg of the desired product.

¹H-NMR (D₆-DMSO) δ=1.95 (3H), 3.85 (3H), 3.9 (3H), 6.6 (1H), 6.7 (1H),6.75 (1H), 7.05 (1H), 7.7 (1H), 7.4-7.5 (2H), 7.6-7.75 (5H) and 9.25(1H) ppm.

Example 645-Chloro-3-hydroxy-3-(2-methoxy-phenyl)-1-(quinoline-8-sulfonyl)-1,3-dihydro-indol-2-one

Potassium tert-butoxide (0.81 g, 7.25 mmol) was added to an ice-coldsolution of Example 28A (2.00 g, 6.90 mmol) in DMF (24 ml), and themixture was stirred at 0° C. for 60 min. After addition of8-quinoline-sulfonyl chloride (1.65 g, 7.25 mmol), the reaction mixturewas left to stir at 0° C. for 2 hours and then at room temperatureovernight. The reaction mixture was stirred into dilute potassiumcarbonate solution, and the resulting precipitate was filtered off,washed with water and dried. Purification by chromatography (silica gel,10% MeOH in dichloromethane) resulted in 1.8 g of the product.

¹H-NMR (D₆-DMSO) δ=2.75 (3H), 6.75 (1H), 6.8 (1H), 7.05 (1H), 7.1 (1H),7.3 (1H), 7.55 (1H), 7.7 (1H), 7.75 (1H), 7.9 (1H), 8.2 (1H), 8.45 (1H),8.6 (1H), 8.65 (1H) and 8.85 (1H) ppm.

Example 65 Piperidine-1-carboxylic acid5-chloro-3-(2-methoxy-phenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester A) Carbonic acid5-chloro-3-(2-methoxy-phenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester phenyl ester

Phenyl chloroformate (0.35 ml, 2.79 mmol) was added dropwise to asolution of Example 64 (300 mg, 0.624 mmol) in pyridine (6 ml) whilecooling slightly. The reaction mixture was stirred at room temperatureovernight. After addition of ice-water, the mixture was extracted withethyl acetate, and the organic phase was washed several times withdilute citric acid solution and water. The organic phase was dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas triturated with diethyl ether, and the resulting precipitate wasfiltered off, washed with diethyl ether and dried. 310 mg of the desiredintermediate were obtained.

B) Piperidine-1-carboxylic acid5-chloro-3-(2-methoxy-phenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester

Piperidine (0.132 ml, 1.33 mmol) was added to a solution of theintermediate from Step A (200 mg, 0.33 mmol) in THF (10 ml), and thereaction solution was stirred overnight. 2 M sodium hydroxide solutionwas added to the reaction mixture, which was then extracted withdichloromethane. The organic phase was washed three times with water andconcentrated under reduced pressure. Recrystallization fromdichloromethane/diethyl ether resulted in 112 mg of the desired product.

¹H-NMR (D₆-DMSO) δ=1.2 (2H), 2.85 (2H), 3.3 (3H), 3.5 (2H), 6.9 (1H),7.05 (1H), 7.1 (1H), 7.35 (1H), 7.5 (1H), 7.6-7.7 (2H), 7.8 (1H), 8.1(1H), 8.4 (1H), 8.55 (1H), 8.6 (1H) and 8.8 (1H) ppm.

Examples 66 to 76 can be prepared in analogous fashion to Example 65Example 66 4-Pyridin-4-yl-piperazine-1-carboxylic acid5-chloro-3-(2-methoxy-phenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester Example 67 3,4,5,6-Tetrahydro-2H-[4,4]bipyridinyl-1-carboxylicacid5-chloro-3-(2-methoxy-phenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester Example 68 4-Pyridin-2-yl-piperazine-1-carboxylic acid5-chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2,4-dimethoxy-pyrimidin-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester Example 69 4-Pyridin-2-yl-piperazine-1-carboxylic acid5-chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester Example 70 4-Pyridin-2-yl-piperazine-1-carboxylic acid5-chloro-3-(2,4-dimethoxy-pyrimidin-5-yl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester Example 71 4-Pyridin-4-yl-piperazine-1-carboxylic acid5-chloro-3-(2,4-dimethoxy-pyrimidin-5-yl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester Example 72 4-Pyridin-2-yl-piperazine-1-carboxylic acid5-chloro-3-(2-methoxy-pyridin-3-yl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester Example 73 4-Pyridin-4-yl-piperazine-1-carboxylic acid5-chloro-3-(2-methoxy-pyridin-3-yl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester Example 74 3,4,5,6-Tetrahydro-2H-[4,4′]bipyridinyl-1-carboxylicacid5-chloro-3-(2-methoxy-pyridin-3-yl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester Example 75 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylicacid5-chloro-3-(2-methoxy-phenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester bismethanesulfonate

¹H-NMR (D₆-DMSO): δ=1.35 (2H), 1.65 (2H), 1.8 (2H), 2.05-2.2 (4H), 2.25(2H), 2.45 (2H), 2.75 (2H), 2.85 (2H), 3.3 (3H), 3.45 (1H), 3.55 (1H),6.90 (1H), 7.05 (1H), 7.15 (1H), 7.35 (1H), 7.5 (1H), 7.6-7.7 (2H), 7.8(1H), 8.10 (1H), 8.4 (1H), 8.55 (1H), 8.65 (1H), 8.8 (1H) and 10.9(broad) ppm.

Example 76 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid1-benzenesulfonyl-5-chloro-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester

¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (2H), 8.10 (2H), 7.80 (2H), 7.70 (2H),7.50 (1H), 7.30 (1H), 7.20 (1H), 3.60 (2H), 3.10 (2H), 2.75 (2H), 2.35(2H), 2.15 (4H), 1.85 (2H), 1.70 (2H), 1.40 (4H); MS (API-ES, pos)m/z=640 [M+H]

Examples 77 to 82 bearing an amide moiety in the 3-position of theoxindole core were prepared employing synthetic methods that areoutlined in synthetic Scheme 3:

Example 77

N-[5-Chloro-3-(2-methoxy-phenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-acetamide

¹H-NMR (D₆-DMSO): δ=1.8 (3H), 3.55 (3H), 6.75 (1H), 7.0 (1H), 7.05 (1H),7.2-7.35 (1H), 7.65 (1H), 7.85 (1H), 7.95 (1H), 8.4 (1H), 8.55 (1H),8.65 (1H), 8.75 (1H) and 8.95 (1H) ppm.

Example 78 3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-carboxylic acid[5-chloro-3-(2-methoxy-phenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-amideExample 79 3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-carboxylic acid[5-chloro-3-(2-methoxy-pyridin-3-yl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-amideExample 80(E)-N-[5-Chloro-3-(2-methoxy-phenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-3-pyridin-4-yl-acrylamide

¹H-NMR (D₆-DMSO): δ=3.85 (3H), 6.45 (1H), 6.65 (1H), 6.85 (1H), 6.9(1H), 7.15, 7.3 (3H), 7.35 (2H), 7.4-7.6 (2H), 7.75 (1H), 8.1-8.3 (4H),8.6 (1H) and 8.75-8.85 (2H) ppm.

Example 81(E)-N-[3-(2-Methoxy-phenyl)-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-3-pyridin-4-yl-acrylamideExample 82 3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-carboxylic acid[5-chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-amide

¹H NMR (400 MHz, DMSO-d₆) δ 9.05 (1H), 8.20 (1H), 8.15 (2H), 7.90 (1H),7.70 (1H), 7.50 (1H), 7.40 (1H), 7.35 (1H), 7.00 (1H), 6.80 (2H), 6.65(2H), 3.80 (8H), 3.50 (3H), 2.90 (2H), 1.75 (1H), 1.60 (1H), 1.35 (2H);MS (API-ES, pos) m/z=678 [M+H]

The procedure for the synthesis of Example 83 is representative for thesynthesis of examples that bear a urea moiety in the 3-position of theoxindole.

Example 83 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid[3-(2-ethoxy-phenyl)-5-methoxy-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-amideA) 3-(2-Ethoxy-phenyl)-3-hydroxy-5-methoxy-1,3-dihydro-indol-2-one

40 g (1.65 mol) of magnesium chips and 5% of the total amount of the2-bromo-1-ethoxy benzene were added to 100 ml diethyl ether and afteradding a few crystals iodine the mixture was carefully heated toinitiate the reaction. To the refluxing mixture the remaining amount of203 ml (1.65 mol) 2-bromo-1-ethoxy benzene, dissolved in 450 ml diethylether, was added slowly to maintain the reaction. Then 75 g (0.41 mol)of 5-methoxyisatine, suspended in 750 ml THF, were added to the cooledreaction mixture. After stirring the reaction mixture for 30 minutes atambient temperature, the mixture was poured into an ice/aqueous NH₄Clmixture. The aqueous phase was extracted with ethyl acetate severaltimes and the combined organic phase was washed with H₂O, dried overmagnesium sulfate and the solvent was removed in vacuo.

B) 3-Chloro-3-(2-ethoxy-phenyl)-5-methoxy-1,3-dihydro-indol-2-one

5 g (16.7 mmol) of the intermediate from Step A and 2.6 g (33.4 mmol)pyridine were dissolved in 50 mL CH₂Cl₂ and at 0° C. 3 g (25.1 mmol)SOCl₂ were added slowly. Then the reaction mixture was stirred for 30min. at 0° C. The reaction mixture was poured into an ice/water mixtureand the organic phase was separated, washed with H₂O, dried overmagnesium sulfate and finally the solvent was removed in vacuo. Theresulting residue was suspended in ether. The solid residue wasseparated and dried to give 3.2 g of the intermediate, which was usedwithout further purification.

C) 3-Amino-3-(2-ethoxy-phenyl)-5-methoxy-1,3-dihydro-indol-2-one

3.2 g (10 mmol) of the intermediate from Step B were suspended in 40 mlCH₂Cl₂. 50 ml of a 2M solution of NH₃ in ethanol were added and thereaction mixture was stirred for 16 h at ambient temperature. Themixture was poured into an ice/water mixture and the precipitate wasseparated. The precipitate was redissolved in ethyl acetate. Thisorganic phase was washed with 2M aqueous HCl. The aqueous phase was madealkaline (pH=8-9) and then extracted with ethyl acetate. The organicphase was dried over magnesium sulfate and the solvent was removed invacuo to yield 1.7 g of the intermediate.

D)[3-(2-Ethoxy-phenyl)-5-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-carbamicacid phenyl ester

1.8 g (6 mmol) of the intermediate from Step C were dissolved in 20 mlpyridine. At 0° C. 0.99 g (6.3 mmol) phenyl chloroformate were added andafterwards the reaction mixture was stirred for 1 h at 0° C. Thismixture was poured into an ice/water mixture. The pH of the aqueousphase was adjusted to 5 and the resulting mixture was extracted withethyl acetate. The organic phase was separated, dried over magnesiumsulfate and the solvent was removed in vacuo. The resulting solid (2 g)was used in the next step without further purification.

E) 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid[3-(2-ethoxy-phenyl)-5-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-amide

1.9 g (4.5 mmol) of the intermediate from Step D and 1.75 g (9.5 mmol)1-(1-methylpiperidine-4-yl)-piperazine were dissolved in 30 ml dry THFand refluxed for 90 minutes. The volatiles were removed in vacuo. Theresulting residue was dissolved in ethyl acetate, washed with H₂O anddried over magnesium sulfate and the solvent was removed in vacuo. Theresidue was treated with H₂O and the resulting precipitate was separatedto yield 1.5 g of the intermediate.

F) 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid[3-(2-ethoxy-phenyl)-5-methoxy-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-amide

200 mg (0.39 mmol) of the intermediate from Step E were dissolved in 30ml THF. At 0° C. 19 mg (0.43 mmol) NaH (55%) were added. After stirringthe reaction mixture for 20 min, 99 mg (0.43 mmol)1-quinoline-8-sulfonylchloride were added. The reaction mixture wasstirred for 1 h. The solvent was removed in vacuo. The residue wasrecrystallized from CH₃OH/H₂O to obtain 180 mg of Example 83.

¹H-NMR (CDCI₃): δ=1.4-1.6 (5H), 1.7 (2H), 1.9 (2H), 2.15-2.35 (4H), 2.45(3H), 2.9 (2H), 3.25 (4H), 3.7 (3H), 4.15 (2H), 6.55 (1H), 6.6 (1H),6.75-6.90 (3H), 7.05-7.2 (2H), 7.40 (1H), 7.65 (1H), 7.9 (1H), 8.0 (1H),8.15 (1H) and 8.85 (1H) ppm.

The following examples bearing a carbamate or urea moiety in the3-position of the oxindole core can be synthesized in analogous fashionto Example 65 or Example 83, respectively.

Example 100 4-Methyl-piperazine-1-carboxylic acid5-chloro-3-(2-methoxy-phenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester

¹H-NMR (D₆-DMSO): S=2.0-2.2 (5H), 2.75 (2H), 2.9 (2H), 3.3 (3H), 3.45(1H), 3.65 (1H), 6.90 (1H), 7.05 (1H), 7.15 (1H), 7.35 (1H), 7.5 (1H),7.6-7.75 (2H), 7.8 (1H), 8.1 (1H), 8.4 (1H), 8.55 (1H), 8.65 (1H) and8.8 (1H) ppm.

Example 101 Dimethyl-carbamic acid5-chloro-3-(2-methoxy-phenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester

¹H-NMR (D₆-DMSO): S=2.45 (3H), 2.95 (3H), 3.3 (3H), 6.90 (1H), 7.05(1H), 7.15 (1H), 7.35 (1H), 7.5 (1H), 7.65 (1H), 7.75 (1H), 7.8 (1H),8.1 (1H), 8.4 (1H), 8.55 (1H), 8.65 (1H) and 8.8 (1H) ppm.

Example 102 [1,4′]Bipiperidinyl-1′-carboxylic acid5-chloro-3-(2-methoxy-phenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester hydrochloride

¹H-NMR (D₆-DMSO): S=1.2-1.4 (4H), 1.6-1.85 (6H), 1.95 (1H), 2.1 (1H),2.6 (1H), 2.8-3.0 (3H), 3.25 (3H), 3.3 (1H), 3.4 (1H), 4.2 (1H), 6.90(1H), 7.05 (1H), 7.15 (1H), 7.35 (1H), 7.5 (1H), 7.6-7.75 (2H), 7.8(1H), 8.15 (1H), 8.4 (1H), 8.55 (2H), 8.6 (1H), 8.8 (1H) and 9.9 (broad)ppm.

Example 103 4-(4-Methyl-piperazin-1-yl)-piperidine-1-carboxylic acid1-benzenesulfonyl-5-chloro-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester

¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (2H), 8.10 (2H), 7.80 (2H), 7.70 (2H),7.50 (1H), 7.27 (1H), 7.20 (1H), 4.20 (1H), 3.55 (1H), 3.05 (1H), 2.65(1H), 2.40 (8H), 2.15 (3H), 1.80 (1H), 1.65 (1H), 1.40 (1H), 1.10 (1H);MS (API-ES, pos) m/z=640 [M+H]

Example 104 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-1-(2,4-dimethoxy-benzenesulfonyl)-2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-indol-3-ylester trishydrochloride

¹H-NMR (D₆-DMSO): δ=2.1 (2H), 2.3 (2H), 2.7 (3H), 2.8-3.9 (18H), 4.4(1H), 6.7 (2H), 7.35 (2H), 7.5 (1H), 7.7-8.0 (4H), 8.3 (1H), and 11.5(broad, N⁺H) and 11.8 (broad, N⁺H) ppm.

Example 105 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester

¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (1H), 8.15 (1H), 7.90 (1H), 7.80 (1H),7.50 (1H), 7.25 (1H), 7.15 (1H), 6.70 (2H), 3.85 (3H), 3.60 (7H), 3.50(1H), 3.10 (2H), 2.80 (2H), 2.30 (2H), 2.15 (4H), 1.80 (2H), 1.65 (2H),1.35 (4H); MS (API-ES, pos) m/z=700 [M+H]

Example 106 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester

¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (1H), 8.10 (1H), 7.90 (1H), 7.75 (1H),7.40 (1H), 7.15 (1H), 7.10 (2H), 6.70 (2H), 3.85 (3H), 3.40-3.70 (8H),3.10 (2H), 2.80 (2H), 2.40 (3H), 2.10 (3H), 1.80 (2H), 1.65 (2H), 1.35(4H); MS (API-ES, pos) m/z=666 [M+H]

Example 107 4-(4-Methyl-piperazin-1-yl)-piperidine-1-carboxylic acid1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-ylester

¹H-NMR (400 MHz, CDCI₃) δ 8.20-8.06 (2H, m), 7.92 (1H, d), 7.82 (1H, d),7.13 (1H, d), 6.94 (1H, t), 6.76 (1H, s), 6.54 (1H, d), 6.43 (1H, s),4.21 (1H, d), 3.85 (6H, d), 3.77 (1H, m), 3.63 (3H, s), 2.92 (1H, t),2.71-2.18 (16H, incl. 2.29) (3H, s), 2.24 (3H, s), 1.64 (4H, s br.); MS(API-ES, pos) m/z=680 [M+H]

Example 108 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-cyano-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-Methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester

¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (2H), 7.90 (3H), 7.75 (1H), 7.17 (1H),6.70 (2H), 3.85 (3H), 3.60 (4H), 3.55 (3H), 3.50 (1H), 3.10 (2H), 2.75(2H), 2.30 (2H), 2.15 (4H), 1.80 (2H), 1.65 (2H), 1.20-1.50 (4H); MS(API-ES, pos) m/z=691 [M+H]

Example 109 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-ylester

¹H-NMR (400 MHz, CDCI₃) δ 8.10 (2H, m), 7.92 (1H, d), 7.79 (1H, d), 7.14(1H, d), 6.94 (1H, m), 6.76 (1H, s), 6.54 (1H, d), 6.41 (1H, s), 3.84(6H, d), 3.63 (3H, s), 3.58 (2H, s br.), 3.17 (2H, br.), 2.92 (2H, d),2.53 (2H, s br.), 2.40 (2H, s br.), 2.26 (3H, s), 2.24 (3H, s), 1.94(2H, t), 1.85-1.47 (8H, m); MS (API-ES, pos) m/z=680 [M+H]

Example 110 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid1-(2,4-dimethoxy-benzenesulfonyl)-5-methoxy-3-(2-methyl-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester trishydrochloride

¹H-NMR (D₆-DMSO): δ=2.1 (2H), 2.3 (2H), 2.7 (6H), 3.0 (2H), 3.15 (1H),3.3-4.0 (18H), 4.3 (1H), 6.6 (1H), 6.7 (1H), 6.9 (1H), 7.15 (1H), 7.3(1H), 7.4 (1H), 7.7 (1H), 7.8 (1H), 8.6 (1H), 10.6 (broad, N⁺H) and 11.6(broad, N⁺H) ppm.

Example 111 4-(1-Methyl-piperidin-4-ye-piperazine-1-carboxylic acid5-chloro-1-(2-fluoro-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester diacetate

MS (ESI, pos) m/z=658 [M+H]

Example 112 4-(1-Methyl-piperidin-4-yl)-piperazine=1-carboxylic acid5-chloro-1-(4-fluoro-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester diacetate

MS (ESI, pos) m/z=658 [M+H]

Example 113 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-1-(4-cyano-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester diacetate

MS (ESI, pos) m/z=665 [M+H]

Example 114 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-1-(3-methoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester diacetate

MS (ESI, pos) m/z=670 [M+H]

Example 115 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-1-(4-methoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester diacetate

MS (ESI, pos) m/z=670 [M+H]

Example 116 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-1-(2-chloro-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester diacetate

MS (ESI, pos) m/z=674 [M+H]

Example 117 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-1-(3-chloro-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester diacetate

MS (ESI, pos) m/z=674 [M+H]

Example 118 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-1-(4-chloro-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester diacetate

MS (ESI, pos) m/z=674 [M+H]

Example 119 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-1-(2,4-difluoro-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester diacetate

MS (ESI, pos) m/z=677 [M+H]

Example 120 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-1-(4-isopropyl-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester diacetate

MS (ESI, pos) m/z=682 [M+H]

Example 121 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-1-(3,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester diacetate

MS (ESL pos) m/z=700 [M+H]

Example 122 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-3-(2-methoxy-pyridin-3-yl)-2-oxo-1-(4-trifluoromethyl-benzenesulfonyl)-2,3-dihydro-1H-indol-3-ylester diacetate

MS (ESI, pos) m/z=708 [M+H]

Example 123 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-3-(2-methoxy-pyridin-3-yl)-2-oxo-1-(4-trifluoromethoxy-benzenesulfonyl)-2,3-dihydro-1H-indol-3-ylester diacetate

MS (ESI, pos) m/z=724 [M+H]

Example 124 Dimethyl-carbamic acid3-benzofuran-7-yl-5-chloro-1-(2,4-dimethoxy-benzenesulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-ylester Example 125 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylicacid[3-(2-ethoxy-phenyl)-5-methoxy-1-(3-methoxy-thiophene-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-amide

¹H-NMR (CDCI₃): δ=1.3 (3H), 1.6-1.8 (2H), 1.8-2.0 (4H), 2.2-2.6 (8h),3.1 (2H), 3.2-3.4 (4H), 3.75 (6H), 4.2 (2H), 6.7-7.0 (7H), 7.2 (1H), 7.5(1H), and 7.8 (1H) ppm.

Example 126 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-methoxy-3-(2-methoxy-phenyl)-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-ylester dihydrochloride

¹H-NMR (D₆-DMSO): S=2.1 (2H), 2.3 (2H), 2.7 (3H), 2.8-3.8 (18H), 4.3(1H), 6.7 (1H), 6.95 (2H), 7.05 (1H), 7.25 (1H), 7.35 (1H), 7.65 (1H),7.95 (1H), 8.15 (1H), 10.8 (broad, N⁺H) and 11.8 (broad, N⁺H) ppm.

Example 127 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid3-(2-methoxy-phenyl)-5-methyl-2-oxo-1-(pyridine-2-sulfonyl)-2,3-dihydro-1H-indol-3-ylester dihydrochloride

¹H-NMR (D₆-DMSO): S=2.0 (2H), 2.15 (3H), 2.3 (2H), 2.7 (3H), 2.9-3.8(15H), 4.3 (1H), 6.85 (1H), 6.90 (1H), 7.1 (1H), 7.2 (1H), 7.35 (1H),7.7 (1H), 7.8 (2H), 8.2 (2H), 10.6 (broad, and 11.7 (broad, N⁺H) ppm.

Example 128 4-(4-Methyl-piperazin-1-yl)-piperidine-1-carboxylic acid3-(2-methoxy-phenyl)-5-methyl-2-oxo-1-(pyridine-2-sulfonyl)-2,3-dihydro-1H-indol-3-ylester dihydrochloride

¹H-NMR (D₆-DMSO): S=1.4 (1H), 1.6 (1H), 2.0 (1H), 2.2 (3H), 2.65 (2H),2.8 (3H), 3.0 (2H), 3.2-3.8 (12H), 4.3 (1H), 6.85 (1H), 6.9 (1H), 7.1(1H), 7.15 (1H), 7.35 (1H), 7.7 (1H), 7.75 (1H), 8.2 (2H), and 8.8 (1H)ppm.

Example 129 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid3-(2-methoxy-phenyl)-5-methyl-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-ylester dihydrochloride

¹H-NMR (D₆-DMSO): S=2.1 (2H), 2.2 (3H), 2.3 (2H), 2.7 (3H), 2.9-3.8(15H), 4.3 (1H), 6.9 (2H), 7.1 (1H), 7.2 (1H), 7.25 (1H), 7.35 (1H), 7.6(1H), 7.8 (1H), 7.95 (1H), 8.1 (1H), 10.6 (broad, N⁺H) and 11.8 (broad,N⁺H) ppm.

Example 130 4-(4-Methyl-piperazin-1-yl)-piperidine-1-carboxylic acid3-(2-methoxy-phenyl)-5-methyl-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-ylester dihydrochloride

¹H-NMR (D₆-DMSO): δ=1.4 (1H), 1.65 (1H), 2.0 (1H), 2.2 (3H), 2.7 (2H),2.8 (3H), 3.0 (2H), 3.2-3.8 (12H), 4.35 (1H), 6.85 (2H), 6.0 (1H), 7.1(1H), 7.15 (1H), 7.25 (1H), 7.35 (1H), 7.6 (1H), 7.8 (1H), 8.0 (1H) and8.1 (1H) ppm.

Example 131 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-methyl-2-oxo-1-(thiophene-2-sulfonyl)-3-o-tolyl-2,3-dihydro-1H-indol-3-ylester dihydrochloride

¹H-NMR (D₆-DMSO): δ=2.0 (2H), 2.2-2.4 (8H), 2.7 (3H), 2.9-3.8 (12H), 4.3(1H), 6.8 (1H), 7.1-7.2 (2H), 7.2-7.4 (4H), 7.7 (1H), 7.85 (1H), 8.1(1H), 10.6 (broad, N⁺H) and 11.8 (broad, N⁺H) ppm.

Example 132 4-(4-Methyl-piperazin-1-yl)-piperidine-1-carboxylic acid5-methyl-2-oxo-1-(thiophene-2-sulfonyl)-3-o-tolyl-2,3-dihydro-1H-indol-3-ylester dihydrochloride

¹H-NMR (D₆-DMSO): δ=1.5 (1H), 2.1 (1H), 2.25-2.4 (6H), 2.7 (2H), 2.8(3H), 3.0 (2H), 3.2-3.9 (10H), 4.25 (1H), 6.75 (1H), 7.0-7.2 (2H),7.2-7.4 (4H), 7.7 (1H), 7.8 (1H) and 8.1 (1H) ppm.

Example 133 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid[3-(2-methoxy-phenyl)-5-methyl-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-amidedihydrochloride

¹H-NMR (D₆-DMSO): δ=2.1 (2H), 2.2 (3H), 2.3 (3H), 2.7 (3H), 2.8-3.7(14H), 3.9 (1H), 4.1 (1H), 6.9-7.1 (4H), 7.25 (1H), 7.3 (1H), 7.5 (1H),7.85 (1H), 7.9 (1H), 8.1 (1H), 10.6 (broad, N⁺H) and 11.4 (broad, N⁺H)ppm.

Example 134 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-cyano-2-oxo-1-(pyridine-2-sulfonyl)-3-o-tolyl-2,3-dihydro-1H-indol-3-ylester dihydrochloride

¹H-NMR (D₆-DMSO): δ=1.9-2.1 (2H), 2.25 (2H), 2.4 (3H), 2.7 (3H), 2.8-3.8(14H), 6.7 (1H), 7.15 (1H), 7.2-7.35 (2H), 7.75 (1H), 7.9 (1H), 8.05(2H), 8.15 (2H), 8.6 (1H), 10.3 (broad, N⁺H) and 11.3 (broad, N⁺H) ppm.

Example 135 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-cyano-2-oxo-1-(thiophene-2-sulfonyl)-3-o-tolyl-2,3-dihydro-1H-indol-3-ylester dihydrochloride

¹H-NMR (D₆-DMSO): S=2.1 (2H), 2.3 (2H), 2.4 (3H), 2.7 (3H), 2.8-3.2(6H), 3.25-3.8 (7H), 4.1-4.4 (1H), 6.75 (1H), 7.15 (1H), 7.2-7.4 (3H),7.9 (1H), 8.0 (2H), 8.05 (1H), 8.2 (1H), 10.8 (broad, N⁺H) and 11.9(broad, N⁺H) ppm.

Example 136 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-fluoro-3-(2-methoxy-phenyl)-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-ylester

¹H NMR (400 MHz, DMSO-d₆) δ 8.15 (1H), 8.00 (1H), 7.80 (1H), 7.75 (1H),7.40 (1H), 7.25 (2H), 7.15 (1H), 7.05 (1H), 6.95 (1H), 3.60 (2H), 3.10(2H), 2.80 (2H), 2.45 (2H), 2.35 (2H), 2.15 (4H), 1.90 (2H), 1.70 (2H),1.40 (2H); MS (API-ES, pos) m/z=629 [M+H]

Example 137 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-methoxy-1-(1-methyl-1H-imidazole-4-sulfonyl)-2-oxo-3-o-tolyl-2,3-dihydro-1H-indol-3-ylester dihydrochloride

¹H-NMR (D₆-DMSO): δ=2.1 (2H), 2.25-2.4 (5H), 2.7 (3H), 2.9-3.1 (4H), 3.2(1H), 3.3-4.0 (13H), 4.3 (1H), 6.7 (1H), 6.8 (1H), 7.1 (2H), 7.2-7.3(2H), 7.7 (2H), 8.1 (1H), 10.6 (broad, N⁺H) and 11.6 (broad, N⁺H) ppm.

Example 138 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-methoxy-3-(2-methoxy-phenyl)-2-oxo-1-(pyridine-2-sulfonyl)-2,3-dihydro-1H-indol-3-ylester dihydrochloride

¹H-NMR (D₂O): δ=1.95 (2H), 2.4 (2H), 2.85 (3H), 3.1 (2H), 3.2-3.8 (16H),4.0 (1H), 6.7 (1H), 6.9 (1H), 7.0 (1H), 7.1 (1H), 7.4 (1H), 7.7-7.9(3H), 8.2 (1H), 8.3 (1H), and 8.7 (1H) ppm.

Example 139 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid3-(2-ethoxy-phenyl)-5-methoxy-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-ylester

¹H-NMR (CDCI₃): δ=1.25 (3H), 1.55 (2H), 1.7 (2H), 1.9 (2H), 2.2-2.35(4H), 2.4 (2H), 2.4-2.6 (2H), 2.9 (2H), 3.05 (2H), 3.6 (2H), 3.7 (3H),3.75 (1H), 3.95 (1H), 6.55 (1H), 6.75 (1H), 6.8 (1H), 7.0 (1H), 7.05(1H), 7.25 (1H), 7.6 (1H), 7.7 (1H), 7.8 (1H) and 7.9 (1H) ppm.

Example 140 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid3-(2-ethoxy-phenyl)-5-methoxy-2-oxo-1-(pyridine-2-sulfonyl)-2,3-dihydro-1H-indol-3-ylester Example 141 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylicacid3-(2-ethoxy-phenyl)-5-methoxy-1-(1-methyl-1H-imidazole-4-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-ylester

¹H-NMR (CDCI₃): δ=1.2 (3H), 1.4-1.7 (4H), 1.75 (2H), 1.9 (2H), 2.2-2.5(7H), 2.6 (2H), 2.9 (2H), 3.1 (1H), 3.25 (1H), 3.6 (2H), 3.7 (3H), 3.75(1H), 4.0 (1H), 6.5 (1H), 6.75 (1H), 6.8 (1H), 7.0 (1H), 7.25 (1H), 7.45(1H), 7.7 (1H), 7.8 (1H) and 7.9 (1H) ppm.

Example 142 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-3-(2-ethoxy-phenyl)-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-ylester

¹H-NMR (CDCI₃): δ=1.25 (3H), 1.45-1.6 (2H), 1.75 (2H), 1.9 (2H), 2.2-2.3(4H), 2.4 (2H), 2.4-2.65 (2H), 2.9 (2H), 2.95-3.15 (2H), 3.6 (2H), 3.8(1H), 4.0 (1H), 6.8 (1H), 6.95 (1H), 7.0 (1H), 7.1 (1H), 7.25-7.35 (2H),7.65 (1H), 7.7 (1H), 7.85 (1H) and 7.9 (1H) ppm.

Example 143 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-3-(2-ethoxy-phenyl)-1-(3-methoxy-thiophene-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-ylester

¹H-NMR (CDCI₃): δ=1.25 (3H), 1.55 (2H), 1.75 (2H), 1.9 (2H), 2.2-2.3(4H), 2.3-2.7 (4H), 2.9 (2H), 3.1 (2H), 3.6 (2H), 3.75 (3H), 3.8 (1H),4.0 (1H), 6.75 (2H), 6.95 (1H), 7.0 (1H), 7.3 (2H), 7.5 (1H), 7.7 (1H)and 7.9 (1H) ppm.

Example 144 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-3-(2-ethoxy-phenyl)-2-oxo-1-(pyridine-2-sulfonyl)-2,3-dihydro-1H-indol-3-ylester

¹H-NMR (CDCI₃): δ=1.25 (3H), 1.5-1.65 (2H), 1.7 (2H), 1.9 (2H), 2.2-2.35(6H), 2.4-2.7 (2H), 2.9 (3H), 3.0 (1H), 3.45-3.6 (2H), 3.8 (1H), 4.0(1H), 6.75 (2H), 6.9 (1H), 7.0 (1H), 7.2-7.4 (3H), 7.5 (1H), 7.65 (1H),7.9 (1H), 8.05 (1H), 8.25 (1H) and 8.7 (1H) ppm.

Example 145 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-3-(2-ethoxy-phenyl)-1-(5-methyl-pyridine-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-ylester

¹H-NMR (CDCI₃): δ=1.3 (3H), 1.5-1.65 (2H), 1.7 (2H), 1.9 (2H), 2.2-2.4(9H), 2.4-2.6 (2H), 2.8-3.0 (3H), 3.05 (1H), 3.6 (2H), 3.8 (1H), 4.0(1H), 6.75 (1H), 6.9 (1H); 7.0 (1H), 7.2-7.4 (2H), 7.65 (2H), 7.65 (1H),8.0 (1H), 8.15 (1H) and 8.5 (1H) ppm.

Example 146 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid[3-(2-ethoxy-phenyl)-5-methoxy-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-amide

¹H-NMR (CDCI₃): δ=1.4-1.6 (5H), 1.75 (2H), 1.9 (2H), 2.15-2.35 (4H),2.4-2.5 (4H), 2.9 (2H), 3.1-3.4 (4H), 3.7 (3H), 4.1-4.3 (2H), 6.75-6.95(6H), 7.05 (1H), 7.25 (1H), 7.6 (1H), 7.75 (1H) and 7.9 (1H) ppm.

Example 147 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid[5-chloro-3-(2-ethoxy-phenyl)-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-amide

¹H-NMR (CDCI₃): δ=1.4-1.65 (5H), 1.75 (2H), 1.9 (2H), 2.2-2.35 (4H),2.8-3.1 (4H), 2.9 (2H), 3.15-3.3 (4H), 4.1-4.3 (2H), 6.6 (1H), 6.8-7.0(2H), 7.0 (1H), 7.1 (1H), 7.2-7.35 (3H), 7.6 (1H), 7.8 (1H) and 7.95(1H) ppm.

Example 148 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid[5-chloro-3-(2-ethoxy-phenyl)-2-oxo-1-(pyridine-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-amidedihydrochloride

¹H-NMR (D₆-DMSO): δ=1.2 (3H), 1.9-2.1 (2H), 2.3 (2H), 2.7 (3H), 2.75-3.6(13H), 3.8-4.0 (2H), 6.95 (2H), 7.2 (1H), 7.25-7.4 (2H), 7.5 (1H), 7.75(2H), 7.9 (1H), 8.15 (2H), 8.8 (1H), 10.4 (broad, N⁺H) and 11.1 (broad,N⁺H) ppm.

Example 149 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid[5-chloro-3-(2-ethoxy-phenyl)-2-oxo-1-(thiophene-3-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-amide

¹H-NMR (CDCI₃): δ=1.4-1.65 (5H), 1.75 (2H), 1.95 (2H), 2.2-2.35 (4H),2.4-2.55 (4H), 2.9 (2H), 3.15-3.3 (4H), 4.1-4.3 (2H), 6.7 (1H), 6.8-6.95(2H), 7.0 (1H), 7.2-7.35 (4H), 7.55 (1H), 7.75 (1H) and 8.35 (1H) ppm.

Example 150 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid[5-chloro-3-(2-ethoxy-phenyl)-1-(5-methyl-pyridine-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-amide

¹H-NMR (CDCI₃): δ=1.4-1.8 (7H), 1.9 (2H), 2.2-2.35 (4H), 2.4-2.55 (7H),2.9 (2H), 3.15-3.35 (4H), 4.1-4.3 (2H), 6.8 (1H), 6.85-6.95 (2H), 7.0(1H), 7.2-7.35 (3H), 7.65 (1H), 7.9 (1H), 8.15 (1H) and 8.50 (1H) ppm.

Example 151 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid3-(2-ethoxy-phenyl)-5-fluoro-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-ylester

¹H-NMR (CDCI₃): δ=1.25 (3H), 1.6 (2H), 1.75 (2H), 2.0 (2H), 2.3 (4H),2.35 (2H), 2.5 (1H), 2.6 (1H), 2.95 (2H), 3.0-3.15 (2H), 3.55 (2H), 3.75(1H), 4.0 (1H), 6.7 (1H), 6.75 (1H), 6.95-7.15 (2H), 7.2-7.4 (2H), 7.6(1H), 7.7 (1H), 7.85 (1H) and 7.9 (1H) ppm.

Example 152 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid3-(2-ethoxy-phenyl)-5-fluoro-1-(5-methyl-pyridine-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-ylester

¹H-NMR (CDCI₃): δ=1.25 (3H), 1.6-1.9 (6H), 2.05 (2H), 2.3-2.6 (9H),2.9-3.2 (4H), 3.55 (2H), 3.8 (1H), 4.05 (1H), 6.65 (1H), 6.75 (1H),6.95-7.1 (2H), 7.25 (1H), 7.65 (1H), 8.0 (1H), 8.15 (1H) and 8.50 (1H)ppm.

Example 153 (2-Diethylamino-ethyl)methyl-carbamic acid5-chloro-3-(2-methoxy-phenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester

¹H-NMR (CDCI₃): δ=0.85 (3H), 1.0 (3H), 2.1 (1H), 2.3 (2H), 2.5-2.7 (3H),2.75 (1H), 2.45 and 3.0 (3H), 3.35 (1H), 3.65 and 3.7 (3H), 6.80 (1H),6.95 (1H), 7.0 (1H), 7.3 (2H), 7.4 (1H), 7.6-7.8 (2H), 8.05 (1H), 8.15(2H) and 8.75-8.9 (2H) ppm.

Example 154 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid3-(2-ethoxy-phenyl)-5-methoxy-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester

¹H-NMR (CDCI₃): δ=1.25 (3H), 1.40-1.8 (6H), 1.90 (2H), 2.10-2.40 (4H),2.45 (2H), 2.80 (2H), 2.9 (2H), 3.5 (2H), 3.70 (3H), 3.8 (1H), 4.1 (1H),6.55 (1H), 6.80 (1H), 6.85-7.0 (2H), 7.25 (1H), 7.40 (1H), 7.60 (2H),8.00 (1H), 8.05-8.2 (2H) and 8.75-8.9 (2H) ppm.

Example 155 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-3-(2-ethoxy-phenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester

¹H-NMR (CDCI₃): δ=1.25 (3H), 1.40-1.8 (6H), 1.90 (2H), 2.10-2.40 (4H),2.45 (2H), 2.70 (2H), 2.9 (2H), 3.5 (2H), 3.8 (1H), 4.05 (1H), 6.80(1H), 6.85-7.0 (2H), 7.25 (1H), 7.3-7.5 (2H), 7.5-7.7 (2H), 8.05 (1H),8.15 (1H), 8.25 (1H) and 8.75 (2H) ppm.

Example 156 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid[5-chloro-3-(2-ethoxy-phenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-amide

¹H-NMR (CDCI₃): δ=1.5 (3H), 1.6 (2H), 1.75 (2H), 1.95 (2H), 2.2-2.35(4H), 2.45 (4H), 2.9 (2H), 3.2 (4H), 4.2 (2H), 6.55 (1H), 6.6 (1H), 6.90(2H), 7.15 (1H), 7.30 (2H), 7.45 (1H), 7.65 (1H), 8.05 (2H), 8.20 (1H),8.75 (1H) and 8.80 (1H) ppm.

Example 157 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid3-(2-ethoxy-phenyl)-5-fluoro-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester

¹H-NMR (CDCI₃): δ=1.25 (3H), 1.4-1.9 (6H), 2.0-2.6 (8H), 2.7 (2H), 3.05(2H), 3.50 (2H), 3.8 (1H), 4.05 (1H), 6.65 (1H), 6.75 (1H), 6.95 (1H),7.1 (1H), 7.30 (1H), 7.40 (1H), 7.60 (1H), 7.65 (1H), 8.05 (1H), 8.15(1H), 8.25 (1H) and 8.75 (2H) ppm.

Example 158 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-cyano-3-(2-ethoxy-phenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester

¹H-NMR (CDCI₃): δ=1.25 (3H), 1.40-1.75 (5H), 1.90 (2H), 2.10-2.30 (5H),2.45 (2H), 2.60 (2H), 2.9 (2H), 3.45 (2H), 3.70 (1H), 4.05 (1H), 6.75(1H), 6.95 (1H), 7.20 (1H), 7.30 (1H), 7.40 (1H), 7.60-7.80 (3H), 8.05(1H), 8.15 (1H), 8.50 (1H), 8.70 (1H) and 8.75 (1H) ppm.

Example 159 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-3-(2-methoxy-pyridin-3-yl)-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-ylester

¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (3H), 8.00 (1H), 7.75 (1H), 7.50 (1H),7.30 (2H), 7.20 (1H), 3.60 (2H), 3.35 (3H), 3.10 (2H), 2.75 (2H), 2.35(2H), 2.10 (4H), 1.80 (2H), 1.65 (2H), 1.35 (4H); MS (API-ES, pos)m/z=646 [M+H]

Example 160 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-methoxy-3-(2-methoxy-pyridin-3-yl)-2-oxo-1-(pyridine-2-sulfonyl)-2,3-dihydro-1H-indol-3-ylester

¹H-NMR (400 MHz, CDCI₃) δ (ppm): 8.73 (1H, d), 8.32 (1H, d), 8.11 (1H,m), 8.00-7.84 (3H, m), 7.56-7.45 (1H, m), 6.94 (1H, t), 6.86 (1H, d),6.52 (1H, s), 3.73 (1H, d), 3.70 (3H, s), 3.56 (2H, s br.), 3.14 (2H, qbr.), 2.94 (2H, d br.), 2.65-1.47 (13H, m br.); MS (API-ES, pos) m/z=637[M+H]

Example 161 4-(4-Methyl-piperazin-1-yl)-piperidine-1-carboxylic acid5-methoxy-3-(2-methoxy-pyridin-3-yl)-2-oxo-1-(pyridine-2-sulfonyl)-2,3-dihydro-1H-indol-3-ylester

¹H-NMR (400 MHz, CDCI₃) δ (ppm): 8.74 (1H, d), 8.32 (1H, d), 8.11 (1H,m), 8.00-7.86 (3H, m), 7.56-7.50 (1H, m), 6.94 (1H, t), 6.86 (1H, d),6.52 (1H, s), 3.73 (3H, s), 3.70 (3H, s), 3.56 (2H, s br.), 3.13 (2H, qbr.), 2.91 (2H, d br.), 2.65-1.39 (13H, m br.); MS (API-ES, pos) m/z=637[M+H]

Example 162 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-cyano-3-(2-methoxy-pyridin-3-yl)-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-ylester

¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (3H), 8.05 (1H), 7.95 (2H), 7.75 (1H),7.30 (1H), 7.20 (1H), 3.60 (2H), 3.10 (2H), 2.80 (2H), 2.35 (2H), 2.15(4H), 2.00 (1H), 1.85 (2H), 1.65 (2H), 1.35 (3H); MS (API-ES, pos)m/z=637 [M+H]

Example 163 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-1-(4,5-dichloro-thiophene-2-sulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester diacetate

MS (ESI, pos) m/z=716 [M+H]

Example 164 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-1-(5-chloro-thiophene-2-sulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester diacetate

MS (ESI, pos) m/z=680 [M+H]

Example 165 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-3-(2-methoxy-pyridin-3-yl)-1-(1-methyl-1H-imidazole-4-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-ylester diacetate

MS (ESI, pos) m/z=646 [M+H]

Example 166 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-1-(1,2-dimethyl-1H-imidazole-4-sulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester diacetate

MS (ESI, pos) m/z=658 [M+H]

Example 167 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-3-(2-methoxy-pyridin-3-yl)-1-(4-methyl-thiophene-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-ylester diacetate

MS (ESI, pos) m/z=660 [M+H]

Example 168 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-3-(2-methoxy-pyridin-3-yl)-1-(5-methyl-thiophene-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-ylester diacetate

MS (ESI, pos) m/z=660 [M+H]

Example 169 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-1-(2,5-dimethyl-thiophene-3-sulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester diacetate

MS (ESI, pos) m/z=674 [M+H]

Example 170 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid1-(benzo[b]thiophene-3-sulfonyl)-5-chloro-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester diacetate

MS (ESI, pos) m/z=696 [M+H]

Example 171 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-3-(2-methoxy-pyridin-3-yl)-2-oxo-1-(thiophene-3-sulfonyl)-2,3-dihydro-1H-indol-3-ylester diacetate

MS (ESI, pos) m/z=646 [M+H]

Example 172 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid

1-(benzo[b]thiophene-2-sulfonyl)-5-chloro-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester diacetate

MS (ESI, pos) m/z=696 [M+H]

Example 173 4-(4-Methyl-piperazin-1-yl)-piperidine-1-carboxylic acid5-chloro-3-(3-methyl-thiophen-2-yl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester dihydrochloride

¹H-NMR (D₆-DMSO): δ=1.4-1.6 (3H), 1.8-2.1 (3H), 2.8-3.6 (15H), 3.7 (1H),4.1 (1H), 6.6 (1H), 6.95 (1H), 7.2-7.4 (3H), 7.55 (2H), 7.95 (1H),8.0-8.2 (2H) and 8.5 (1H) ppm.

Example 174 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-chloro-3-(3-methyl-thiophen-2-yl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester

¹H-NMR (CDCI₃): δ=1.4 (2H), 1.65 (2H), 1.8-2.0 (5H), 2.05-2.15 (4H),2.35 (2H), 2.45 (2H), 2.8 (2H), 3.05 (2H), 3.4 (2H), 6.8 (1H), 7.3 (1H),7.4 (1H), 7.55 (1H), 7.65 (1H), 7.8 (1H), 8.0 (1H), 8.4 (1H), 8.5 (2H)and 8.6 (1H) ppm.

Example 175

Benzyl-methyl-carbamic acid5-chloro-3-(2-methoxy-phenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester

Example 176 4-Benzyl-piperazine-1-carboxylic acid5-chloro-3-(2-methoxy-phenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester Example 177 4-Methyl-piperazine-1-carboxylic acid5-chloro-3-(2-methoxy-phenyl)-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-ylester Example 178 Pyridin-4-ylmethyl-carbamic acid5-chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(3-methyl-thiophen-2-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester Example 179

Benzyl-carbamic acid5-chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(3-methyl-thiophen-2-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester

Example 180 Pyridin-4-ylmethyl-carbamic acid5-chloro-3-(2-methoxy-phenyl)-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-ylester Example 181 (3-Imidazol-1-yl-propyl)-carbamic acid5-chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(3-methyl-thiophen-2-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester Example 182 (3-Morpholin-4-yl-propyl)-carbamic acid5-chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(3-methyl-thiophen-2-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester Example 183 4-Benzoylamino-piperidine-1-carboxylic acid5-chloro-3-(2-methoxy-phenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester Example 184 3-Phenyl-piperidine-1-carboxylic acid5-chloro-3-(2-methoxy-phenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester Example 185 1,3-Dihydro-isoindole-2-carboxylic acid5-chloro-3-(2-methoxy-phenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester Example 186 4-Phenyl-piperidine-1-carboxylic acid5-chloro-3-(2-methoxy-phenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester Example 187 (2-Diethylamino-ethyl)-carbamic acid5-chloro-3-(2-methoxy-phenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester hydrochloride Example 188 (2-Dimethylamino-ethyl)-carbamic acid5-chloro-3-(3-methyl-thiophen-2-yl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester Example 189 4-Methyl-piperazine-1-carboxylic acid5-chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(3-methyl-pyridin-2-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester Example 190 Dimethyl-carbamic acid5-chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(3-methyl-pyridin-2-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester Example 191 (2-Pyridin-4-yl-ethyl)-carbamic acid5-chloro-3-(3-methyl-thiophen-2-yl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester Example 192 6-Methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylicacid5-chloro-3-(2-methoxy-phenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester Example 193 (4-Cyano-thiazol-2-ylmethyl)-carbamic acid5-chloro-3-(2-methoxy-phenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester Example 194 Dimethyl-carbamic acid5-chloro-3-(2,4-dimethoxy-pyrimidin-5-yl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester Example 195 4-Isopropyl-piperazine-1-carboxylic acid5-chloro-3-(2,4-dimethoxy-pyrimidin-5-yl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-ylester Example 196 (5-Dimethylamino-pentyl)-carbamic acid1-benzenesulfonyl-5-chloro-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester Example 197 4-(2-Morpholin-4-yl-ethyl)-piperazine-1-carboxylicacid1-benzenesulfonyl-5-chloro-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester Example 198 4-(2-Imidazol-1-yl-ethyl)-piperazine-1-carboxylic acid1-benzenesulfonyl-5-chloro-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester Example 199 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylicacid3-benzofuran-7-yl-5-chloro-1-(2,4-dimethoxy-benzenesulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-ylester dihydrochloride Example 2004-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid2-oxo-1-(thiophene-2-sulfonyl)-3-o-tolyl-2,3-dihydro-1H-indol-3-yl esterdihydrochloride Example 2014-(4-Methyl-piperazin-1-yl)-piperidine-1-carboxylic acid2-oxo-1-(thiophene-2-sulfonyl)-3-o-tolyl-2,3-dihydro-1H-indol-3-yl esterdihydrochloride Example 2024-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid1-(2,4-dimethyl-thiazole-5-sulfonyl)-5-methoxy-2-oxo-3-o-tolyl-2,3-dihydro-1H-indol-3-ylester dihydrochloride Example 2034-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid1-(2,5-dimethyl-thiophene-3-sulfonyl)-3-(2-isopropoxy-phenyl)-5-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl-esterdihydrochloride Example 2044-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid3-(2-isopropoxy-phenyl)-5-methoxy-1-(1-methyl-1H-imidazole-4-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-ylester dihydrochloride Example 2054-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid1-(2,5-dimethyl-thiophene-3-sulfonyl)-3-(2-ethoxy-phenyl)-5-methoxy-2-oxo-2,3-dihydro-1H-indol-3-ylester dihydrochloride Example 2064-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid1-(2,5-dimethyl-thiophene-3-sulfonyl)-5-methoxy-2-oxo-3-(2-propoxy-phenyl)-2,3-dihydro-1H-indol-3-ylester dihydrochloride Example 2074-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-methoxy-2-oxo-3-(2-propoxy-phenyl)-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-ylester dihydrochloride Example 2084-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid3-(2-ethoxy-phenyl)-5-fluoro-1-(1-methyl-1H-Imidazole-4-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-ylester Example 209 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylicacid1-(1,2-dimethyl-1H-imidazole-4-sulfonyl)-3-(2-ethoxy-phenyl)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylester Example 210 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylicacid1-(3,5-dimethyl-isoxazole-4-sulfonyl)-3-(2-ethoxy-phenyl)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylester Example 211 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylicacid1-(2,5-dimethyl-thiophene-3-sulfonyl)-3-(2-ethoxy-phenyl)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylester Example 212 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylicacid3-(2-ethoxy-phenyl)-5-fluoro-1-(3-methoxy-thiophene-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-ylester Example 213 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylicacid1-(2,4-dimethyl-thiazole-5-sulfonyl)-3-(2-ethoxy-phenyl)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylester dihydrochloride Example 2144-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid[1-(3,5-dimethyl-isoxazole-4-sulfonyl)-3-(2-ethoxy-phenyl)-5-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-amideExample 215 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid[1-(5-chloro-thiophene-2-sulfonyl)-3-(2-ethoxy-phenyl)-5-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-amideExample 216 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid[1-(2,5-dimethyl-thiophene-3-sulfonyl)-3-(2-ethoxy-phenyl)-5-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-amideExample 217 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylic acid5-cyano-3-(2-ethoxy-phenyl)-2-oxo-1-(thiophene-3-sulfonyl)-2,3-dihydro-1H-indol-3-ylester Example 218 4-(1-Methyl-piperidin-4-yl)-piperazine-1-carboxylicacid[5-cyano-3-(2-ethoxy-phenyl)-2-oxo-1-(thiophene-3-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-amidedihydrochloride

Unless stated otherwise, the following examples bearing amines in the3-position of the oxindole core can be synthesized according tosynthesis Scheme 1 in analogous fashion to Examples 1 to 6.

The amide derivatives of amino acids were acquired from commercialsuppliers or synthesized according to standard methods, for exampleaccording to the following procedure:

(S)—N,N-Dimethyl-2-methylamino-propionamide hydrochloride

To a solution of (S)-Boc-N-Me-Ala-OH (9.8 mmol, 2.00 g, from Bachem) inDMF (10 mL) were added 1-Hydroxy-1H-benzotriazole (10.8 mmol, 1.46 g)and EDCI (10.8 mmol, 2.08 g). The reaction mixture was stirred for 10min before a 2M solution of dimethylamine in THF (11.8 mmol, 5.9 mL) wasadded. After stirring for 18 h at room temperature, water was added andthe mixture was extracted several times with ethyl acetate. The combinedorganic layers were washed with 1N aqueous hydrochloric acid, aqueoussodium bicarbonate solution and water. After drying over magnesiumsulfate, the volatiles were removed in vacuo. Yield: 1.86 g of acolorless oil (82%). The Boc-protected coupling product was dissolved inMeOH (19 mL) and treated with a 4N solution of HCl in dioxane (32.3mmol, 8.1 mL). After stirring for 18 h at room temperature, the reactionmixture was evaporated to dryness to leave 1.41 g of a white solid(quantitative yield).

(S)-Pyrrolidine-2-carboxylic acid dimethylamide hydrochloride,(S)-Pyrrolidine-2-carboxylic acid methylamide hydrochloride,(S)-Piperidine-2-carboxylic acid dimethylamide hydrochloride,(S)-Azetidine-2-carboxylic acid dimethylamide hydrochloride,(S)-2,5-Dihydro-1H-pyrrole-2-carboxylic acid dimethylamidehydrochloride, (2S,4R)-4-Fluoro-pyrrolidine-2-carboxylic aciddimethylamide hydrochloride, (2S,4S)-4-Hydroxy-pyrrolidine-2-carboxylicacid dimethylamide hydrochloride,(2S,4R)-4-Hydroxy-piperidine-2-carboxylic acid dimethylamidehydrochloride, N,N-Dimethyl-2-methylamino-acetamide hydrochloride,2-Amino-N,N-dimethyl-acetamide hydrochloride, Pyrrolidine-3-carboxylicacid dimethylamide hydrochloride, (S)-2-Amino-N,N-dimethyl-propionamidehydrochloride, (S)-2-Amino-N,N-dimethyl-butyramide hydrochloride wereprepared in analogous fashion.

Example 220(S)-2-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-methyl-amino)-N,N-dimethyl-propionamide,levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.1, CHCI₃): −197;

¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (1H), 7.95 (2H), 7.85 (1H), 7.50 (1H),7.15 (1H), 6.90 (1H), 6.75 (2H), 4.00 (1H), 3.85 (3H), 3.75 (3H), 3.25(3H), 2.75 (3H), 2.35 (3H), 0.90 (3H); MS (API-ES, pos) m/z=603 [M+H]

Example 221(S)-2-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-N,N-dimethyl-propionamide,levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.1, CHCI₃): −152;

¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (1H), 8.10 (1H), 7.95 (1H), 7.85 (1H),7.50 (1H), 7.10 (1H), 7.00 (1H), 6.80 (1H), 6.75 (1H), 3.90 (3H), 3.80(3H), 3.40 (2H), 3.25 (3H), 2.75 (3H), 2.65 (3H), 0.90 (3H); MS (API-ES,pos) m/z=589 [M+H]

Example 222(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(3-methyl-pyridin-2-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H-NMR (D₆-DMSO): S=1.65 (1H), 1.9 (3H), 2.0 (1H), 2.45 (3H), 2.6 (3H),2.65 (1H), 3.3 (1H), 3.5 (3H), 3.9 (3H), 4.3 (1H), 4.7 (1H), 5.6 (1H),6.7 (1H), 6.75 (1H), 7.1 (1H), 7.25 (1H), 7.45 (1H), 7.55 (1H), 7.75(1H), 7.95 (1H) and 8.15 (1H) ppm.

Example 223(2S,4R)-1-[1-Benzenesulfonyl-5-chloro-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H NMR (400 MHz, DMSO-d₆) δ 8.45 (1H), 8.25 (1H), 8.10 (1H), 7.70-7.90(4H), 7.45 (1H), 7.10 (1H), 7.05 (1H), 5.00 (1H), 4.45 (1H), 4.27 (1H),3.25 (1H), 2.95 (3H), 2.70 (1H), 2.40 (3H), 2.05 (1H), 1.70 (1H); MS(API-ES, pos) m/z=571 [M+H]

Example 224(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-2-oxo-3-(2-oxo-1,2-dihydro-pyridin-3-yl)-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carlboxylicacid dimethylamide, levorotatory diastereomer

A solution of Example 5 (0.16 mmol, 100 mg) and sodium iodide (0.32mmol, 109 mg) in acetic acid (1 mL) was heated overnight at 40° C. Thereaction mixture was diluted with ethyl acetate and washed with aqueoussodium dithionate solution, water and brine. The organic layer was driedover magnesium sulfate and concentrated in vacuo. Chromatographicpurification over silica gel (gradient from 4% to 12% MeOH indichloromethane) yielded 59 mg (60%) of a white crystalline solid.

¹H NMR (400 MHz, DMSO-d₆) δ 11.55 (1H), 7.90 (2H), 7.70 (1H), 7.40 (1H),7.30 (1H), 7.00 (1H), 6.70 (1H), 6.65 (1H), 6.70 (1H), 4.90 (1H), 4.60(1H), 4.30 (1H), 3.85 (3H), 3.55 (3H), 2.90 (1H), 2.60 (3H), 2.55 (3H),2.25 (1H), 1.60 (1H); MS (API-ES, pos) m/z=617 [M+H]

Example 225(2S,4R)-1-[1-(2,4-Dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.1, CHCI₃): −285;

¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (1H), 8.10 (1H), 8.00 (1H), 7.80 (1H),7.37 (1H), 6.90-7.15 (3H), 6.77 (1H), 6.70 (1H), 4.90 (1H), 4.55 (1H),4.45 (1H), 3.85 (3H), 3.70 (3H), 3.40 (3H), 2.85 (1H), 2.60 (3H), 2.35(3H), 2.15 (1H), 1.30-1.70 (2H); MS (API-ES, pos) m/z=597 [M+H]

Example 226

(S)-1-[1-(2,4-Dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.1, CHCI₃): −210;

¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (2H), 7.95 (1H), 7.80 (1H), 7.40 (1H),7.15 (1H), 7.00 (2H), 6.77 (2H), 4.50 (1H), 3.87 (3H), 3.65 (3H), 3.50(3H), 2.70 (3H), 2.40 (3H), 2.20 (1H), 1.75 (1H), 1.40 (3H); MS (API-ES,pos) m/z=581 [M+H]

Example 227(S)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.1, CHCI₃): −242;

¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (2H), 7.95 (1H), 7.80 (1H), 7.50 (1H),7.05 (2H), 6.80 (2H), 4.50 (1H), 3.87 (3H), 3.70 (3H), 3.50 (3H), 2.75(1H), 2.70 (3H), 2.45 (3H), 2.20 (1H), 1.75 (1H), 1.40 (3H); MS (API-ES,pos) m/z=615 [M+H]

Example 228(2S,4R)-1-[1-(2,4-Dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide fumarate, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.1, CHCI₃): −200;

¹H-NMR (400 MHz, DMSO-d₆) δ 8.15 (1H, s br.), 8.07 (1H, m), 7.97 (1H,d), 7.67 (1H, d), 7.17 (1H, d), 7.01 (1H, t), 6.86-6.66 (3H, m), 4.87(1H, s), 4.56 (1H, d), 4.34 (1H, sext.), 3.86 (3H, s), 3.70 (3H, s),2.59 (3H, s br.), 2.35 (3H, s), 2.21 (3H, s), 1.60 (1H, m); MS (API-ES,pos) m/z=611 [M+H]

Example 229(2S,4R)-1-[1-Benzenesulfonyl-3-(2-methoxy-pyridin-3-yl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide fumarate, levorotatory diastereomer

¹H-NMR (400 MHz, CDCI₃) δ 8.27 (1H, d), 8.22 (2H, s br.), 8.03 (1H, m),7.79 (1H, d), 7.68 (1H, t), 7.60 (2H, m), 7.10 (1H, d), 6.90 (1H, t),6.77 (1H, s), 4.74 (1H, s br.), 4.55 (1H, m), 3.22 (3H, s br.), 2.73(3H, s br.), 2.42 (3H, s br.), 2.20 (3H, s), 1.94 (1H, m), 1.84 (1H, sbr.); MS (API-ES, pos) m/z=551 [M+H]

Example 230(2S,4R)-1-[1-(2,4-Dimethoxy-benzenesulfonyl)-5-methoxy-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide fumarate, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.1, CHCI₃): −137;

¹H-NMR (500 MHz, DMSO-d₆) δ 8.17 (1H, d), 8.06 (1H, d), 7.99 (1H, d),7.70 (1H, d), 7.00 (1H, t), 6.94 (1H, d), 6.72 (1H, d), 6.70 (1H, s),6.47 (1H, s), 4.70 (1H, s br.), 4.58 (1H, d), 4.36 (1H, s br.), 3.86(3H, s), 3.72 (3H, s), 3.67 (3H, s), 3.42 (3H, s), 2.94 (1H, s br.),2.60 (3H, m), 2.38 (3H, m), 2.20 (1H, s br.), 1.66-1.47 (2H, m); MS(API-ES, pos) m/z=627 [M+H]

Example 231(2S,4R)-1-[1-Benzenesulfonyl-5-methoxy-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide fumarate, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.1, CHCI₃): −192;

¹H-NMR (500 MHz, DMSO-d₆) δ 8.37 (1H, m), 8.17 (2H, d), 8.02 (1H, m),7.76 (1H, t), 7.68 (2H, t), 7.62 (1H, d), 7.02 (1H, t), 6.90 (1H, d),6.44 (1H, s), 4.80 (1H, s br.), 4.47 (1H, m), 4.30 (1H, s br.), 3.64(3H, s), 3.04 (3H, s), 2.60 (1H, m br.), 2.44 (6H, s), 1.96 (1H, s br.),1.70 (1H, m); MS (API-ES, pos) m/z=567 [M+H]

Example 232(2S,4R)-1-[5-Cyano-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid, dimethylamide, levorotatory diastereomer A)3-Hydroxy-5-iodo-3-(2-methoxy-pyridin-3-yl)-1,3-dihydro-indol-2-one

A 1.7 M solution of tert-butyllithium in pentane (35 ml, 60 mmol) wasadded to THF (100 ml) at −78° C. 2-Bromomesitylene (4.6 ml, 30 mmol) wasadded dropwise and the mixture stirred at −78° C. for 1 h.2-Methoxypyridine (3.2 ml, 30 mmol) was added at −78° C. and then themixture was stirred at 0° C. for 1.5 h. The ice-cold solution of thelithiated 2-methoxypyridine was transferred (via a transfer needle) intoan ice-cold suspension of 5-iodoisatin (4.1 g, 15 mmol) in THF (150 ml).The reaction mixture was allowed to warm to room temperature and thensaturated ammonium chloride solution was added. The mixture wasextracted three times with ethyl acetate, and the collected extractswere washed with saturated brine. The organic phase was dried overmagnesium sulfate, filtered and concentrated under reduced pressure.Purification by crystallization from dichloromethane yielded 2.9 g ofthe intermediate.

MS (API-ES, pos) m/z=383 [M+H]

B)(2S,4R)-4-Hydroxy-1-[5-iodo-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-carboxylicacid dimethylamide

The chlorination/amination sequence was performed as described forExamples 5 and 6 (Steps B and C). The two diastereomers were separatedby flash chromatography over silica gel (gradient from 4% to 10% MeOH indichloromethane). The major diastereomer was the later eluting one andled to the required levorotatory product.

MS (API-ES, pos) m/z=523 [M+H]

C)(2S,4R)-1-[1-(2,4-Dimethoxy-benzenesulfonyl)-5-iodo-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

The sulfonylation was performed as described for Example 5 (Step D).

MS (API-ES, pos) m/z=723 [M+H]

D) Example 232(2S,4R)-1-[5-Cyano-1-(2,4-Dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

A solution of Example 232C (0.69 mmol, 500 mg), zinc zyanide (0.69 mmol,81 mg) and palladium(0)-tetrakis-triphenylphosphine (15 mg) in DMF (3mL) was heated at 75° C. for 24 h. The reaction mixture was poured intowater and extracted with ethyl acetate. The organic layer was washedwith water and brine. After drying over magnesium sulfate, the volatileswere evaporated in vacuo. The remaining oil was triturated withdichloromethane and the white solid was collected by filtration. Thecrude product was purified by flash chromatography over silica gel(gradient from 4% to 10% MeOH in dichloromethane). Yield: 315 mg of thedesired product as a white solid (73%).

¹H NMR (400 MHz, DMSO-d₆) δ 8.32 (1H), 8.08 (1H), 8.00 (1H), 7.92 (1H),7.86 (1H), 7.54 (1H), 7.05 (1H), 6.72-6.80 (2H), 4.98 (1H), 4.55 (1H),4.32 (1H), 3.88 (3H), 3.73 (3H), 3.03 (1H), 2.45 (3H), 1.55-1.80 (2H);MS (API-ES, pos) m/z=622 [Mi-H]

Example 233(S)-1-[5-Cyano-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-carboxylicacid dimethylamide, 1:1 mixture of diastereomers

MS (API-ES, pos) m/z=606 [M+H]

Example 234(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(3-methoxy-pyridin-4-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer A)5-Chloro-3-hydroxy-3-(3-methoxy-pyridin-4-yl)-1,3-dihydro-indol-2-one

A 1.7 M solution of tert-butyllithium in pentane (57.8 mL) was added toTHF (200 ml) at −78° C. 2-Bromomesitylene (3.6 mL) was added dropwise,keeping the temperature below −60° C., and the mixture stirred at −78°C. for 1 h. 3-Methoxypyridine (3.6 mL) was added dropwise at −78° C. andthen the mixture was allowed to warm to −5° C. over 2 h. The reactionmixture was re-cooled to −78° C. and a slurry of 5-chloroisatin (3.26 g)in THF (100 mL) was added portionwise keeping the temperature below −60°C. The reaction mixture was stirred at −78° C. for 1 h. The cooling bathwas removed and the reaction mixture was stirred for 30 min. Thereaction mixture was quenched with 10% aqueous ammonium chloridesolution and extracted several times with ethyl acetate. The combinedorganic layers were washed with water, dried over magnesium sulfate andevaporated to low volume. Upon standing, 0.73 g of a pale yellow solidseparated which was filtered off, washed with ethyl acetate and dried invacuo.

The subsequent steps were performed in analogous fashion to Examples 5and 6.

Example 234

[α]_(D) ^(20° C). (c=0.1, CHCI₃): −212;

¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (2H), 8.00 (1H), 7.85 (1H), 7.75 (1H),7.45 (1H), 7.00

(1H), 6.75 (2H), 4.95 (1H), 4.55 (1H), 4.35 (1H), 3.85 (3H), 3.75 (3H),3.40 (3H), 3.00 (1H), 2.55 (3H), 2.40 (3H), 2.30 (1H), 1.65 (1H); MS(API-ES, pos) m/z=631 [M+H]

Example 235(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.1, CHCI₃): −23;

¹H-NMR (400 MHz, CDCI₃) δ 8.13 (1H, d), 8.06 (1H, d), 7.99 (1H, d), 7.88(1H, d), 7.70 (1H, t), 7.09 (1H, m), 6.61 (1H, dd), 6.47 (1H, s), 4.35(1H, s br.), 3.98 (3H, m), 3.89 (3H, s), 3.54 (dd, 1H), 3.46 (3H, s),2.74 (3H, s), 2.67 (1H, d), 2.55 (3H, s), 2.11 (1H, m), 1.91 (1H, m); MS(API-ES, pos) m/z=601 [M+H]

Example 236(2S,4R)-1-[5-Chloro-3-(2,4-dimethoxy-pyrimidin-5-yl)-1-(4-methoxy-benzenesulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H NMR (400 MHz, DMSO-d₆) δ 8.95 (1H), 8.10 (2H), 7.70 (1H), 7.40 (1H),7.20 (3H), 5.05 (1H), 4.40° (1H), 4.25 (1H), 3.85 (6H), 3.25 (1H), 3.15(3H), 2.75 (1H), 2.35 (3H), 2.00 (1H), 1.65 (1H); MS (API-ES, pos)m/z=632 [M+H]

Example 237(S)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.1, CHCI₃): −195;

¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (1H), 8.05 (1H), 7.95 (1H), 7.85 (1H),7.50 (1H), 7.15 (1H), 6.85 (1H), 6.75 (2H), 3.70-3.95 (8H), 2.95 (3H),2.65 (3H), 2.20 (3H), 1.85 (1H), 1.30-1.70 (5H); MS (API-ES, pos)m/z=629 [M+H]

Example 238(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2,6-dimethoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer A)5-Chloro-3-hydroxy-3-(2,6-dimethoxy-pyridin-3-yl)-1,3-dihydro-indol-2-one

To a stirred solution of 2,6-dimethoxypyridine (50 mmol, 6.61 mL) in THF(100 mL) was added slowly a 1.6 M solution of n-butyllithium in hexanes(55 mmol, 34.4 mL) at −78° C. The mixture was allowed to warm slowly to10° C. and kept at this temperature for 30 min. The reaction mixture wasre-cooled to −78° C. and a slurry of 5-chloroisatin (20 mmol, 3.63 g) inTHF (150 mL) was added portionwise, keeping the temperature below −60°C. The reaction was allowed to come to room temperature. The mixture wasquenched with 10% aqueous ammonium chloride solution and extractedseveral times with ethyl acetate. The combined organic layers werewashed with water, dried over magnesium sulfate and evaporated in vacuo.Recrystallization from ethyl acetate yielded 4.56 g (71%) of the desiredintermediate as a white crystalline solid (71%).

MS (API-ES, pos) m/z=321 [M+H]

The subsequent steps were performed as described for Example 5 andExample 6.

Example 238

¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (1H), 8.00 (1H), 7.80 (1H), 7.45 (1H),7.00 (1H), 6.75 (2H), 6.40 (1H), 4.90 (1H), 4.55 (1H), 4.30 (1H), 3.85(3H), 3.80 (3H), 3.70 (3H), 3.40 (3H), 2.90 (1H), 2.55 (3H), 2.45 (3H),2.20 (1H), 1.60 (2H); MS (API-ES, pos) m/z=661 [M+H]

Example 239(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-ethoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

Example 239 was synthesized in analogy to Example 5, substituting2-methoxypyridine with 2-ethoxypyridine in Step A.

[α]_(D) ^(20° C). (c=0.1, CHCI₃): −228;

¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (1H), 8.10 (1H), 8.00 (1H), 7.80 (1H),7.45 (1H), 7.00 (2H), 6.75 (2H), 4.95 (1H), 4.55 (1H), 4.30 (1H), 3.95(2H), 3.85 (3H), 3.70 (3H), 2.90 (1H), 2.55 (3H), 2.45 (3H), 2.25 (1H),1.60 (1H), 0.80 (3H); MS (API-ES, pos) m/z=645 [M+H]

Example 240(2S,4R)-1-[5-Chloro-1-(4-methoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H NMR (400 MHz, DMSO-d₆) δ 8.40 (1H), 8.15 (2H), 8.05 (1H), 7.70 (1H),7.40 (1H), 7.20 (2H), 7.10 (1H), 7.00 (1H), 5.00 (1H), 4.45 (1H), 4.30(1H), 3.85 (3H), 3.20 (1H), 3.05 (3H), 2.65 (1H), 2.40 (3H), 2.05 (1H),1.65 (1H); MS (API-ES, pos) m/z=601 [M+H]

Example 241(2S,4R)-1-[5-Chloro-1-(2-methoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide levorotatory diastereomer

¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (1H), 8.10 (2H), 7.75 (2H), 7.45 (1H),7.30 (1H), 7.20 (1H), 7.05 (2H), 4.95 (1H), 4.55 (1H), 4.35 (1H), 3.75(3H), 3.00 (1H), 2.55 (3H), 2.45 (3H), 2.25 (1H), 1.65 (2H); MS (API-ES,pos) m/z=601 [M+H]

Example 242(2S,4R)-1-[5-Cyano-1-(4-methoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (1H), 8.15 (2H), 8.10 (1H), 7.85 (2H),7.50 (1H), 7.20 (2H), 7.10 (1H), 5.05 (1H), 4.45 (1H), 4.30 (1H), 3.85(3H), 3.20 (1H), 3.05 (3H), 2.70 (1H), 2.35 (3H), 2.05 (1H), 1.65 (1H);MS (API-ES, pos) m/z=592 [M+H]

Example 243(2S,4R)-1-[1-(2,4-Dimethoxy-benzenesulfonyl)-5-iodo-3-(3-methoxy-pyrazin-2-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.1, CHCI₃): −9;

¹H-NMR (400 MHz, CDCI₃) δ 8.17 (1H, d), 8.12 (2H, dd), 7.72 (1H, d),7.63 (1H, d), 7.16 (1H, s), 6.58 (1H, dd), 6.51 (1H, s), 5.48 (1H, sbr.), 4.71 (1H, t), 4.26 (1H, s), 3.83 (6H, d), 3.59 (3H, s), 3.32 (1H,dd), 3.10 (1H, d), 2.88 (3H, s), 2.56 (3H, s), 2.22 (1H, m sym.), 1.74(1H, m sym.)

Example 244(2S,4R)-1-[1-(2,4-Dimethoxy-benzenesulfonyl)-3-(2,4-dimethoxy-pyrimidin-5-yl)-5-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (1H), 8.00 (1H), 7.65 (1H), 6.95 (1H),6.75 (2H), 6.60 (1H), 4.90 (1H), 4.60 (1H), 4.30 (1H), 3.85 (6H), 3.70(6H), 3.40 (3H), 3.00 (1H), 2.55 (3H), 2.45 (3H), 2.25 (1H), 1.65 (1H);MS (API-ES, pos) m/z=658 [M+H]

Example 245(2S,4R)-1-[1-(2,4-Dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-5-trifluoromethoxy-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (1H), 8.10 (1H), 8.00 (1H), 7.90 (1H),7.45 (1H), 7.05 (1H), 7.00 (1H), 6.80 (1H), 6.75 (1H), 4.95 (1H), 4.55(1H), 4.35 (1H), 3.85 (3H), 3.70 (3H), 3.40 (3H), 2.90 (1H), 2.60 (3H),2.40 (3H), 2.20 (1H), 1.65 (1H); MS (API-ES, pos) m/z=681 [M+H]

Example 246(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.1, CHCI₃): −207;

¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (1H), 8.10 (1H), 8.00 (1H), 7.75 (1H),7.45 (1H), 7.10 (2H), 6.75 (2H), 5.25 (1H), 4.60 (1H), 3.85 (3H), 3.75(3H), 3.40 (1H), 3.25 (3H), 2.85 (1H), 2.45 (6H), 2.30 (1H), 1.85 (1H);MS (API-ES, pos) m/z=633 [M+H]

Example 247(S)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2,5-dihydro-1H-pyrrole-2-carboxylicacid dimethylamide, mixture of diastereomers

MS (API-ES, pos) m/z=613 [M+H]

Example 248(S)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-carboxylicacid methyl ester, mixture of diastereomers Example 249(S)-1-[5-Chloro-3-(6-chloro-2-methoxy-pyridin-3-yl)-1-(2,4-dimethoxy-benzenesulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-carboxylicacid dimethylamide, mixture of diastereomers Example 250(2S,4R)-1-[1-(Benzo[b]thiophene-3-sulfonyl)-5-chloro-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide trifluoroacetate

MS (ESI, pos) m/z=626 [M+H]

Example 251(2S,4R)-1-[5-Chloro-3-(2-methoxy-phenyl)-1-(2-methyl-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

Sodium acetoxyborohydride (0.36 mmol, 76.27 mg) was added to a solutionof Example 61 (0.24 mmol, 0.15 g), acetic acid (0.24 mmol, 14.4 mg) andaq. formaldehyde (37%, 0.26 mmol, 21.42 mg). The mixture was stirred atRT for 12 h and evaporated in vacuo. The residue was solved in H₂O andextracted with ethyl acetate. The organic phase was dried, filtrated andevaporated. The crude product was then purified on a column of silicageleluted with 5% MeOH in CH₂Cl₂ to afford 100 mg of the required product.

[α]_(D) ^(20° C). (c=0.1, CHCI₃): −112;

MS (API-ES, pos) m/z=639 [M+H]

Example 252(2S,4R)-1-[5-Chloro-3-(2-methoxy-phenyl)-1-(4-methyl-pyridine-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H NMR (400 MHz, DMSO-d₆) δ 8.65 (1H), 8.20 (1H), 8.00 (1H), 7.80 (1H),7.65 (1H), 7.45 (1H), 7.30 (1H), 7.00 (1H), 6.95 (1H), 6.85 (1H), 4.95(1H), 4.50 (1H), 4.30 (1H), 3.10 (3H), 2.40 (3H), 2.00 (1H), 1.65 (1H);MS (API-ES, pos) m/z=585 [M+H]

Example 253(2S,4R)-1-[5-Chloro-3-(2-methoxy-phenyl)-1-(6-methyl-pyridine-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (1H), 8.10 (1H), 8.00 (1H), 7.80 (1H),7.65 (1H), 7.40 (1H), 7.30 (1H), 7.00 (1H), 6.95 (1H), 6.85 (1H), 4.90(1H), 4.50 (1H), 4.30 (1H), 3.15 (3H), 2.55 (3H), 2.40 (4H), 1.60 (1H);MS (API-ES, pos) m/z=585 [M+H]

Example 254(2S,4R)-1-[5-Fluoro-3-(2-methoxy-phenyl)-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H NMR (400 MHz, DMSO-d₆) δ 8.15 (1H), 8.10 (1H), 8.00 (1H), 7.70 (1H),7.30 (2H), 7.20 (1H), 7.00 (1H), 6.80 (2H), 4.95 (1H), 4.50 (1H), 4.30(1H), 2.95 (4H), 2.45 (3H), 2.00 (1H), 1.70 (1H); MS (API-ES, pos)m/z=560 [M+H]

Example 255(S)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-azetidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (1H), 8.05 (2H), 7.85 (1H), 7.50 (1H),7.00 (2H), 6.80 (2H), 4.80 (1H), 3.90 (3H), 3.75 (3H), 3.50 (3H), 2.80(1H), 2.65 (4H), 2.35 (4H), 1.60 (1H); MS (API-ES, pos) m/z=601 [M+H]

Example 256(2S,4R)-1-[5-Chloro-3-(2-methoxy-phenyl)-1-(3-methoxy-thiophene-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.1, CHCI₃): −149;

¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (1H), 7.85 (1H), 7.75 (1H), 7.40 (1H),7.30 (1H), 7.15 (1H), 7.00 (1H), 6.90 (2H), 4.95 (1H), 4.55 (1H), 4.35(1H), 3.85 (3H), 3.25 (3H), 2.35 (4H), 1.65 (1H); MS (API-ES, pos)m/z=606 [M+H]

Example 270(2S,4R)-1-[5-Chloro-3-(2-methoxy-pyridin-3-yl)-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.1, CHCI₃): −110;

¹H NMR (400 MHz, DMSO-d₆) δ 8.45 (1H), 8.17 (1H), 8.07 (2H), 7.70 (1H),7.43 (1H), 7.30 (1H), 7.03-7.15 (2H), 5.03 (1H), 4.45 (1H); 4.30 (1H),3.25, 3.05 (3H), 2.70 (1H), 2.40 (3H), 2.05 (1H), 1.70 (1H); MS (API-ES,pos) m/z=577 [M+H]

Example 271(2S,4R)-4-Hydroxy-1-[3-(2-methoxy-pyridin-3-yl)-1-(5-methyl-pyridine-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H NMR (400 MHz, DMSO-d₆) δ 8.85 (1H), 8.40 (1H), 8.00 (1H), 7.75 (1H),7.45 (1H), 7.05 (1H), 6.95 (1H), 6.75 (2H), 4.95 (1H), 4.60 (1H), 4.35(1H), 3.85 (3H), 3.75 (3H), 3.35 (3H), 3.00 (1H), 2.55 (3H), 2.45 (3H),1.60 (2H); MS (API-ES, pos) m/z=552 [M+H]

Example 272(2S,4R)-4-Hydroxy-1-[3-(2-methoxy-pyridin-3-yl)-5-methyl-2-oxo-1-(pyridine-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-carboxylicacid dimethylamide fumarate, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.1, CHCI₃): −166;

¹H-NMR (500 MHz, DMSO-d₆) δ 8.79 (1H, d), 8.42 (2H, m), 8.28 (1H, t),8.05 (1H, d), 7.77 (1H, m), 7.68 (1H, d), 7.14 (1H, d), 7.04 (1H, t),6.77 (1H, s), 4.80 (1H, s), 4.44 (1H, m), 4.33 (1H, m), 3.25 (3H, s),3.15 (3H, s), 2.58 (1H, s br.), 2.43 (3H, s), 2.39 (3H, s), 2.19 (3H,s), 1.85 (1H, s br.), 1.66 (1H, m); MS (API-ES, pos) m/z=552 [M+H]

Example 273(2S,4R)-4-Hydroxy-1-[3-(2-methoxy-pyridin-3-yl)-5-methyl-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-carboxylicacid dimethylamide fumarate, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.1, CHCI₃): −157;

¹H-NMR (400 MHz, CDCI₃) δ 8.25 (1H, s br.), 8.03 (2H, m), 7.72 (2H, m),7.18 (1H, t), 7.09 (1H, d), 6.91 (1H, t), 6.81 (1H, s), 4.76 (1H, sbr.), 4.57 (1H, m), 3.35 (3H, s br.), 2.72 (3H, s br.), 2.45 (3H, s),2.22 (3H, s), 1.96 (2H, m); MS (API-ES, pos) m/z=557 [M+H]

Example 274(2S,4R)-4-Hydroxy-1-[3-(2-methoxy-pyridin-3-yl)-5-methyl-1-(5-methyl-pyridine-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-carboxylicacid dimethylamide fumarate, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.1, CHCI₃): −209;

¹H-NMR (400 MHz, CDCI₃) δ 8.54 (1H, s), 8.30 (1H, d), 8.20 (1H, s br.),8.03 (1H, m), 7.80 (2H, m), 7.08 (1H, d), 6.90 (1H, t), 6.83 (1H, s),4.74 (1H, s br.), 4.58 (1H, quint.), 3.58 (3H, s br.), 2.72 (3H, s br.),2.44 (3H, s), 2.41 (3H, s), 2.21 (3H, s), 1.88 (1H, m), 1.68 (4H, s); MS(API-ES, pos) m/z=566 [M+H]

Example 275(2S,4R)-4-Hydroxy-1-[5-methoxy-3-(2-methoxy-pyridin-3-yl)-2-oxo-1-(pyridine-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl)-pyrrolidine-2-carboxylicacid dimethylamide fumarate, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.1, CHCI₃): −105;

¹H-NMR (400 MHz, DMSO-d₆) δ 8.81 (1H, d), 8.31 (1H, d), 8.22 (1H, t),8.05 (1H, d), 7.82 (1H, m), 6.94 (1H, d), 6.48 (1H, s), 4.96 (1H, sbr.), 4.47 (1H, s br.), 4.31 (1H, s br.), 3.66 (3H, s), 3.17 (3H, m),2.38 (3H, s), 1.63 (1H, m); MS (API-ES, pos) m/z=568 [M+H]

Example 276(2S,4R)-4-Hydroxy-1-[5-methoxy-3-(2-methoxy-pyridin-3-yl)-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-carboxylicacid dimethylamide fumarate, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.1, CHCI₃): −175;

¹H-NMR (400 MHz, DMSO-d₆) δ 8.41 (1H, s br.), 8.15 (1H, d), 8.04 (2H,m), 7.60 (1H, d), 7.30 (1H, t), 7.07 (1H, t), 6.92 (1H, d), 6.47 (1H,s), 4.99 (1H, s br.), 4.47 (1H, s br.), 4.31 (1H, s br.), 3.65 (3H, s),3.02 (3H, s), 2.41 (6H, s), 2.00 (1H, m br.), 1.69 (1H, m); MS (API-ES,pos) m/z=573 [M+H]

Example 277(2S,4R)-1-[5-Cyano-3-(2-methoxy-pyridin-3-yl)-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (1H), 8.20 (1H), 8.15 (1H), 8.10 (1H),7.85 (2H), 7.55 (1H), 7.35 (1H), 7.10 (1H), 5.05 (1H), 4.50 (1H), 4.30(1H), 3.30 (1H), 3.05 (3H), 2.75 (1H), 2.35 (3H), 2.05 (1H), 1.70 (1H);MS (API-ES, pos) m/z=568 [M+H]

Example 278(S)-1-[5-Chloro-3-(2-methoxy-pyridin-3-yl)-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.1, CHCI₃): −242;

¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (1H), 8.10 (2H), 8.05 (1H), 7.75 (1H),7.45 (1H), 7.35 (1H), 7.10 (2H), 4.40 (1H), 3.10 (3H), 3.05 (1H), 2.00(1H), 1.60-1.90 (2H); MS (API-ES, pos) m/z=561 [M+H]

Example 279(2S,4R)-4-Hydroxy-1-[5-methoxy-3-(2-methoxy-pyridin-3-yl)-1-(5-methyl-pyridine-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-carboxylicacid dimethylamide fumarate m/z=582 [M+H] Example 280(2S,4R)-1-[5-Chloro-3-(2,6-dimethoxy-pyridin-3-yl)-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H NMR (400 MHz, DMSO-d₆) δ 8.30 (1H), 8.20 (1H), 8.10 (1H), 7.70 (1H),7.40 (1H), 7.30 (1H), 7.05 (1H), 6.45 (1H), 5.00 (1H), 4.45 (1H), 4.30(1H), 3.80 (3H), 3.25 (1H), 3.05 (3H), 2.70 (1H), 2.40 (3H), 2.00 (1H),1.65 (1H); MS (API-ES, pos) m/z=607 [M+H]

Example 281(2S,4R)-1-[5-Chloro-3-(2,4-dimethoxy-pyrimidin-5-yl)-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H NMR (400 MHz, DMSO-d₆) δ 8.95 (1H), 8.20 (1H), 8.10 (1H), 7.70 (1H),7.45 (1H), 7.30 (1H), 7.25 (1H), 5.05 (1H), 4.45 (1H), 4.25 (1H), 3.90(3H), 3.15 (3H), 2.80 (1H), 2.35 (3H), 2.05 (1H), 1.65 (1H); MS (API-ES,pos) m/z=608 [M+H]

Example 282(2S,4R)-1-[5-Chloro-3-(2,4-dimethoxy-pyrimidin-5-yl)-1-(5-methyl-pyridine-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (1H), 8.65 (1H), 8.20 (1H), 8.05 (1H),7.75 (1H), 7.45 (1H), 7.25 (1H), 5.05 (1H), 4.40 (1H), 4.25 (1H), 3.90(3H), 3.25 (3H), 2.70 (1H), 2.45 (3H), 2.35 (3H), 2.00 (1H), 1.65 (1H);MS (API-ES, pos) m/z=617 [M+H]

Example 283(2S,4R)-4-Hydroxy-1-[5-iodo-3-(3-methoxy-pyrazin-2-yl)-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.1, CHCI₃): −11;

¹H-NMR (400 MHz, CDCI₃) δ 8.14 (3H, m), 7.73 (1H, m), 7.66 (2H, s), 7.19(1H, t), 7.12 (1H, s), 5.54 (1H, s br.), 4.58 (1H, t), 4.25 (1H, s),3.40 (3H, s), 3.29 (1H, dd), 3.17 (1H, d), 2.80 (3H, s), 2.52 (3H, s),2.27 (1H, m sym.), 1.70 (1H, m sym.); MS (API-ES, pos) m/z=671 [M+H]

Example 284(2S,4R)-4-Hydroxy-1-[5-iodo-3-(3-methoxy-pyrazin-2-yl)-1-(5-methyl-pyridine-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.1, CHCI₃): −8;

¹H-NMR (400 MHz, CDCI₃) δ 8.55 (1H, s), 8.38 (1H, d), 8.12 (2H, m), 7.80(2H, t), 7.65 (1H, d), 7.15 (1H, s), 4.56 (1H, t), 4.24 (1H, s), 3.52(3H, s), 3.30 (1H, dd), 3.12 (1H, d), 2.77 (3H, s), 2.47 (6H, d), 2.26(1H, m sym.), 1.71 (1H, m sym.); MS (API-ES, pos) m/z=679 [M+H]

Example 285(2S,4R)-1-[5-Chloro-3-(2-methoxy-pyridin-3-yl)-1-(3-methoxy-thiophene-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (1H), 8.10 (2H), 7.80 (1H), 7.45 (1H),7.20 (1H), 7.05 (1H), 7.00 (1H), 5.00 (1H), 4.50 (1H), 4.35 (1H), 3.90(1H), 3.25 (3H), 3.15 (1H), 2.45 (3H), 1.85 (1H), 1.65 (1H); MS (API-ES,pos) m/z=607 [M+H]

Example 286(2S,4R)-4-Hydroxy-1-[3-(2-methoxy-pyridin-3-yl)-1-(3-methoxy-thiophene-2-sulfonyl)-2-oxo-5-trifluoromethoxy-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (1H), 8.10 (1H), 7.85 (1H), 7.40 (1H),7.20 (1H), 7.05 (1H), 6.95 (1H), 5.00 (1H), 4.50 (1H), 4.35 (1H), 3.90(3H), 3.25 (3H), 3.15 (1H), 2.40 (3H), 1.85 (1H), 1.70 (1H); MS (API-ES,pos) m/z=657 [M+H]

Example 287(2S,4R)-1-[5-Chloro-3-(2,4-dimethoxy-pyrimidin-5-yl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, mixture of the two diastereomers

MS (API-ES, pos) m/z=653 [M+H]

Example 288(2S,4R)-1-[5-Chloro-3-(2-methoxy-pyridin-3-yl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

¹H NMR (400 MHz, DMSO-d₆) δ 8.85 (1H), 8.75 (1H), 8.60 (1H), 8.45 (1H),8.30 (1H), 8.20 (1H), 8.05 (1H), 7.90 (1H), 7.70 (1H), 7.50 (1H), 7.00(2H), 4.80 (1H), 4.55 (1H), 4.30 (1H), 3.05 (1H), 2.67 (3H), 1.55-1.90(2H); MS (API-ES, pos) m/z=622 [M+H]

Example 289(2S,4R)-1-[5-Chloro-3-(2,4-dimethoxy-pyrimidin-5-yl)-1-(5-methyl-pyridine-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

[α]_(D) ^(20° C). (c=0.1, CHCI₃): −178;

¹H NMR (400 MHz, DMSO-d₆) δ 8.65 (1H), 8.40 (1H), 8.25 (1H), 8.10 (1H),8.00 (1H), 7.80 (1H), 7.45 (1H), 7.05 (2H), 5.00 (1H), 4.45 (1H), 4.30(1H), 3.20 (3H), 2.65 (1H), 2.45 (3H), 2.40 (3H), 2.38, 2.00 (1H), 1.65(1H); MS (API-ES, pos) m/z=586 [M+H]

Example 3025-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-3-pyrrolidin-1-yl-1,3-dihydro-indol-2-oneExample 3035-Chloro-3-(1,3-dihydro-isoindol-2-yl)-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-1,3-dihydro-indol-2-oneExample 3045-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3((R)-3-hydroxy-pyrrolidin-1-yl)-3-(2-methoxy-pyridin-3-yl)-1,3-dihydro-indol-2-oneExample 3053-Amino-5-chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-1,3-dihydro-indol-2-oneExample 306(2S,4R)-4-Hydroxy-1-[3-(2-methoxy-pyridin-3-yl)-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 3075-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3((S)-2-methoxymethyl-pyrrolidin-1-yl)-3-(2-methoxy-pyridin-3-yl)-1,3-dihydro-indol-2-one,levorotatory diastereomer Example 308(S)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-carboxylicacid amide, levorotatory diastereomer Example 3092-{[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-methyl-amino}-N,N-dimethyl-acetamideExample 3102-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-N,N-dimethyl-acetamideExample 311(2S,4R)-1-[5-Chloro-3-(3-methyl-pyridin-2-yl)-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide methanesulfonate, levorotatory diastereomer Example312(2S,4R)-1-[5-Chloro-1-(5-methyl-pyridine-2-sulfonyl)-3-(3-methyl-pyridin-2-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide methanesulfonate, levorotatory diastereomer Example3135-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-34(S)-2-trifluoromethyl-pyrrolidin-1-yl)-1,3-dihydro-indol-2-one,levorotatory diastereomer Example 3145-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-34(S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-1,3-dihydro-indol-2-one,levorotatory diastereomer Example 315(S)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-carboxylicacid tert-butyl ester, levorotatory diastereomer Example 3165-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-3-[(S)-2-(4-methyl-piperazine-1-carbonyl)-pyrrolidin-1-yl]-1,3-dihydro-indol-2-one,levorotatory diastereomer Example 317(S)-4-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-3-dimethylcarbamoyl-piperazine-1-carboxylicacid tert-butyl ester, levorotatory diastereomer Example 318(2S,4R)-1-[5-Chloro-3-(2-ethoxy-pyridin-3-yl)-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 320(S)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperazine-2-carboxylicacid dimethylamide trifluoroacetate Example 321(2S,4R)-1-[5-Cyano-3-(2-methoxy-pyridin-3-yl)-1-(5-methyl-pyridine-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 3225-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-3-[(S)-2-(pyrrolidine-1-carbonyl)-pyrrolidin-1-yl]-1,3-dihydro-indol-2-one,levorotatory diastereomer Example 324(2S,4R)-1-[5-Chloro-3-(2,4-dimethoxy-pyrimidin-5-yl)-1-(3-methoxy-thiophene-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 325(S)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-carboxylicacid methylamide Example 3261-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-3-carboxylicacid dimethylamide, mixture of diastereomers Example 3275-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-dimethylamino-1-methyl-ethylamino)-3-(2-methoxy-pyridin-3-yl)-1,3-dihydro-indol-2-one,levorotatory diastereomer Example 328(S)-1-[5-Cyano-1-(4-methoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 329(S)-1-[5-Cyano-3-(2-methoxy-pyridin-3-yl)-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 330(S)-2-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-N,N-dimethyl-butyramide,levorotatory diastereomer Example 331(S)-1-[5-Chloro-1-(4-methoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 332(2S,4R)-1-[5-Chloro-1-(4-methoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 334(2S,4R)-1-[5-Chloro-3-(2,6-dimethoxy-pyridin-3-yl)-1-(4-methoxy-benzenesulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 3351-[5-Cyano-3-(2-methoxy-phenyl)-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-carboxylicacid dimethylamide, mixture of diastereomers Example 336(2S,4R)-1-[5-Chloro-3-(2-ethoxy-phenyl)-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, mixture of diastereomers Example 337(2S,4R)-1-[5-Chloro-3-(2-ethoxy-phenyl)-1-(5-methyl-pyridine-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 339(2S,4R)-1-[5-Cyano-3-(2-methoxy-phenyl)-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, mixture of diastereomers Example 340(2S,4R)-1-[5-Cyano-3-(2-methoxy-phenyl)-1-(5-methyl-pyridine-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, mixture of diastereomers Example 341(2S,4R)-1-[3-(2-Ethoxy-phenyl)-5-methoxy-1-(5-methyl-pyridine-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, mixture of diastereomers Example 342(2S,4R)-1-[5-Cyano-3-(2-methoxy-phenyl)-2-oxo-1-(thiophene-3-sulfonyl)-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, mixture of diastereomers Example 343(S)-2-{[5-Cyano-1-(4-methoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-methyl-amino}-N,N-dimethyl-propionamide,mixture diastereomers Example 344(S)-2-{[5-Cyano-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-methyl-amino}-N,N-dimethyl-propionamide,mixture of diastereomers Example 345(S)-2-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-3,N,N-trimethyl-butyramide,levorotatory diastereomer Example 346(S)-1-[5-Cyano-1-(4-methoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 347(S)-1-[5-Cyano-3-(2-methoxy-pyridin-3-yl)-1-(5-methyl-pyridine-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 348(2S,4R)-4-Hydroxy-1-[1-(4-methoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-5-trifluoromethoxy-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 349(S)-1-[5-Cyano-3-(2-methoxy-pyridin-3-yl)-1-(5-methyl-pyridine-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 350(S)-1-[5-Chloro-3-(2-methoxy-pyridin-3-yl)-1-(5-methyl-pyridine-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 3512-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-2,N,N-trimethyl-propionamideExample 352(2S,4R)-1-[5-Cyano-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 353(2S,4R)-1-[5-Cyano-1-(4-methoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 354(2S,4R)-1-[5-Cyano-3-(2-methoxy-pyridin-3-yl)-1-(5-methyl-pyridine-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 355(2S,4R)-1-[5-Chloro-3-(2-ethoxy-pyridin-3-yl)-1-(4-methoxy-benzenesulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, mixture of diastereomers Example 356(S)-2-{[5-Chloro-1-(4-methoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-methyl-amino}-N,N-dimethyl-propionamide,levorotatory diastereomer Example 357(S)-2-{[5-Chloro-3-(2-methoxy-pyridin-3-yl)-1-(5-methyl-pyridine-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-methyl-amino}-N,N-dimethyl-propionamide,levorotatory diastereomer Example 358(2S,4R)-1-[5-Chloro-3-(2-methoxy-pyridin-3-yl)-1-(5-methyl-pyridine-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 3593-[(S)-2-(Azetidine-1-carbonyl)-pyrrolidin-1-yl]-5-chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-1,3-dihydro-indol-2-one,levorotatory diastereomer Example 360(S)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-carboxylicacid ethyl-methyl-amide, levorotatory diastereomer Example 361(2S,4S)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 362(2S,4S)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyrdin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 363(2S,4S)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-phenoxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 364(2S,4S)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 365(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 366(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-phenoxy-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 367(S)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4,4-difluoro-pyrrolidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 368(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-piperidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 369(2S,4S)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoro-piperidine-2-carboxylicacid dimethylamide, levorotatory diastereomer Example 370(S)-1-[5-Chloro-1-(2,4-dimethoxy-benzenesulfonyl)-3-(2-methoxy-pyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4,4-difluoro-piperidine-2-carboxylicacid dimethylamide, levorotatory diastereomer

In the following Table 2 characteristic mass-spectroscopic data areshown for selected examples.

TABLE 2 Characteristic mass-spectroscopic data for selected examples(ESI, positive mode) Example # Molecular ion peak 1 657 2 657 3 662 4662 5 631 6 631 9 631 10 631 13 632 28 621 29 576 30 576 31 610 32 69033 690 35 646 37 626 38 674 39 574 40 588 41 622 42 602 43 650 44 589 45605 46 650 47 571 48 649 53 663 54 599 55 571 56 656 57 663 59 684 60641 61 625 62 480 63 633 64 481 65 592 66 670 68 711 70 702 75 690

The invention claimed is:
 1. A method for treating a disorder selectedfrom the group consisting of depressive and/or bipolar disorders, andanxiety and/or stress-related disorders, the method comprisingadministering to a mammal in need thereof a therapeutically effectiveamount of a compound of formula (I),

in which A is an aromatic heteromonocyclic ring, where the heterocyclesare 5- or 6-membered rings and comprise up to 4 heteroatoms selectedfrom the group consisting of N, O and S, and up to 2 oxo groups, wherenot more than one of the heteroatoms is an oxygen atom, and A may besubstituted by radicals R¹¹, R¹²and/or R¹³, where R¹¹, R¹² and R¹³ ateach occurrence are selected independently of one another from the groupconsisting of hydrogen, chlorine, bromine, iodine, fluorine, CN, CF₃,OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, phenyl,C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) andN(C₁-C₄-alkyl)₂, R³ and R⁴ are selected independently of one anotherfrom the group consisting of hydrogen, chlorine, bromine, iodine,fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl,O—C₁-C₄-alkylen-phenyl, phenyl, C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂, or R³ and R⁴are connected to give —CH═CH—CH═CH—, —(CH₂)₄— or —(CH₂)₃—, R⁵ is aradical (W)—(X)—(Y)—Z, where W is a bond, X is NR⁵⁴—CO, Y isC₁-C₆-alkylen, C₂-C₆-alkenylen, C₂-C₆-alkynylen, or a bond, Z isselected from the group consisting of hydrogen, E, O—R⁵², NR⁵¹R⁵², andS—R⁵², where E is an unsaturated, saturated or partially unsaturatedmono-, bi- or tricyclic ring having a maximum of 14 carbon atoms and 0to 5 nitrogen atoms, 0 to 2 oxygen atoms and/or 0 to 2 sulfur atoms,said ring may comprise up to two oxo groups, and may be substituted byradicals R⁵⁵, R⁵⁶, R⁵⁷, and/or up to three radicals R⁵³, R⁵¹ at eachoccurrence is independently selected from the group consisting ofhydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl andC₁-C₄-alkylen-phenyl, where the phenyl ring may be substituted by up totwo radicals R⁵³, R⁵² at each occurrence is independently selected fromthe group consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkynyl, E and C₁-C₄-alkylen-E, R⁵³ at each occurrence isindependently selected from the group consisting of hydrogen, chlorine,bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH, O—C₁-C₄-alkyl,C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) andN(C₁-C₄-alkyl)₂, R⁵⁴ at each occurrence is independently selected fromthe group consisting of hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkynyl, phenyl and C₁-C₄-alkylen-phenyl, where the phenyl ringmay be substituted by up to two radicals R⁵⁹, R⁵⁵ at each occurrence isindependently selected from the group consisting of hydrogen,C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl, C₁-C₄-alkylen-phenyl;where the ring may be substituted by up to two radicals R⁶⁰, and OH,O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, NH₂, NH(C₁-C₄-alkyl)and N(C₁-C₄-alkyl)₂, R⁵⁶ is a group Q¹-Q²-Q³, where Q¹ is selected fromthe group consisting of a bond, C₁-C₄-alkylen, C₂-C₄-alkenylen,C₂-C₄-alkynylen, C₁-C₄-alkylen-N(C₁-C₄-alkyl), N(C₁-C₄-alkyl),C₁-C₄-alkylen-NH, NH, N(C₁-C₄-alkyl)-C₁-C₄-alkylen, NH—C₁-C₄-alkylen, O,C₁-C₄-alkylen-O, O—C₁-C₄-alkylen, CO—NH, CO—N(C₁-C₄-alkyl), NH—CO,N(C₁-C₄-alkyl)-CO, CO, SO₂, SO, S, O, SO₂—NH, SO₂—N(C₁-C₄-alkyl),NH—SO₂, N(C₁-C₄-alkyl)-SO₂, O—CO—NH, O—CO—N(C₁-C₄-alkyl), NH—CO—O,N(C₁-C₄-alkyl)-CO—O, N(C₁-C₄-alkyl)-CO—N(C₁-C₄-alkyl),NH—CO—N(C₁-C₄-alkyl), N(C₁-C₄-alkyl)-CO—NH, and NH—CO—NH, Q² is selectedfrom the group consisting of C₁-C₄-alkylen, C₂-C₄-alkenylen,C₂-C₄-alkynylen, and a bond, Q³ is a hydrogen or an unsaturated,saturated or partially unsaturated mono-, bi- or tricyclic ring having amaximum of 14 carbon atoms and 0 to 5 nitrogen atoms, 0 to 2 oxygenatoms and/or 0 to 2 sulfur atoms, which may comprise up to two oxogroups and may be substituted by the radicals R⁶³, R⁶⁴ and/or R⁶⁵, R⁵⁷at each occurrence is independently selected from the group consistingof hydrogen, C₁-C₆-alkyl, phenyl, C₁-C₄-alkylen-phenyl, COOH,CO—O—C₁-C₄-alkyl, CONH₂, CO—NH—C₁-C₄-alkyl, CO—N(C₁-C₄-alkyl)₂,CO—C₁-C₄-alkyl, CH₂—NH₂, CH₂—NH—C₁-C₄-alkyl and CH₂—N(C₁-C₄-alkyl)₂, R⁵⁸at each occurrence is independently selected from the group consistingof hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, phenyl andC₁-C₄-alkylen-phenyl, where the phenyl ring may be substituted by up totwo radicals R⁶², R⁵⁹, R⁶⁰ and R⁶² at each occurrence are selectedindependently of one another from the group consisting of hydrogen,chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH,O—C₁-C₄-alkyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂,NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂, R⁶³, R⁶⁴ and R⁶⁵ at each occurrenceare selected independently of one another from the group consisting ofhydrogen, chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, NO₂, OH,O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, phenyl, C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) and N(C₁-C₄-alkyl)₂,R⁶ and R⁷ are selected independently of one another from the groupconsisting of hydrogen, chlorine, bromine, iodine, fluorine, CN, CF₃,OCF₃, NO₂, OH, O—C₁-C₄-alkyl, O-phenyl, O—C₁-C₄-alkylen-phenyl, phenyl,C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, NH₂, NH(C₁-C₄-alkyl) andN(C₁-C₄-alkyl)₂, and their tautomeric forms, enantiomeric anddiastereomeric forms, and prodrugs thereof.
 2. The method of claim 1,wherein the disorder is a depressive and/or bipolar disorder, selectedfrom the group consisting of a dysthymic disorder, subsyndromaldepression, a seasonal affected disorder, a premenstrual dysphoricdisorder, and a psychotic disorder.
 3. The method of claim 1, whereinthe disorder is an anxiety and/or stress-related disorder, selected fromthe group consisting of a general anxiety disorder, a panic disorder, anobsessive-compulsive disorder, a post-traumatic disorder, an acutestress disorder, and a social phobia.
 4. The method of claim 1, whereinthe disorder is depression.
 5. The method of claim 1, wherein thedisorder is general anxiety disorder.